|
Effective concentration for gametocidal activity against Plasmodium falciparum FDL-HD
|
Plasmodium falciparum
|
0.115
ug well-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Isolation and antimalarial activity of peroxydisulfate oxidation products of primaquine.
Year : 2002
Volume : 12
Issue : 24
First Page : 3587
Last Page : 3589
Authors : Dua VK, Sinha SN, Biswas S, Valecha N, Puri SK, Sharma VP.
Abstract : Five compounds formed by peroxydisulfate oxidation of primaquine were isolated using chromatographic methods and evaluated for antimalarial activity in vitro. One compound 6-methoxy-5,8 bis(4'-amino-1'-methylbutylamino)quinoline [P(1)] was found to have good gametocytocidal activity against Plasmodium yoelli infected mice at 10mg kg(-1) dose in vivo.
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum D6
|
Plasmodium falciparum
|
2.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, antimalarial, antileishmanial, antimicrobial, cytotoxicity, and methemoglobin (MetHB) formation activities of new 8-quinolinamines.
Year : 2007
Volume : 15
Issue : 2
First Page : 915
Last Page : 930
Authors : Kaur K, Patel SR, Patil P, Jain M, Khan SI, Jacob MR, Ganesan S, Tekwani BL, Jain R.
Abstract : We report the synthesis, in vitro antiprotozoal (against Plasmodium and Leishmania), antimicrobial, cytotoxicity (Vero and MetHb-producing properties), and in vivo antimalarial activities of two series of 8-quinolinamines. N1-{4-[2-(tert-Butyl)-6-methoxy-8-quinolylamino]pentyl}-(2S/2R)-2-aminosubstitutedamides (21-33) and N1-[4-(4-ethyl-6-methoxy-5-pentyloxy-8-quinolylamino)pentyl]-(2S/2R)-2-aminosubstitutedamides (51-63) were synthesized in six steps from 6-methoxy-8-nitroquinoline and 4-methoxy-2-nitro-5-pentyloxyaniline, respectively. Several analogs displayed promising antimalarial activity in vitro against Plasmodium falciparum D6 (chloroquine-sensitive) and W2 (chloroquine-resistant) clones with high selectivity indices versus mammalian cells. The most promising analogs (21-24) also displayed potent antimalarial activity in vivo in a Plasmodium berghei-infected mouse model. Most interestingly, many analogs exhibited promising in vitro antileishmanial activity against Leishmania donovani promastigotes, and antimicrobial activities against a panel of pathogenic bacteria and fungi. Several analogs, notably 21-24, 26-32, and 60, showed less MetHb formation compared to primaquine indicating the potential of these compounds in 8-quinolinamine-based antimalarial drug development.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum W2
|
Plasmodium falciparum
|
2.8
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, antimalarial, antileishmanial, antimicrobial, cytotoxicity, and methemoglobin (MetHB) formation activities of new 8-quinolinamines.
Year : 2007
Volume : 15
Issue : 2
First Page : 915
Last Page : 930
Authors : Kaur K, Patel SR, Patil P, Jain M, Khan SI, Jacob MR, Ganesan S, Tekwani BL, Jain R.
Abstract : We report the synthesis, in vitro antiprotozoal (against Plasmodium and Leishmania), antimicrobial, cytotoxicity (Vero and MetHb-producing properties), and in vivo antimalarial activities of two series of 8-quinolinamines. N1-{4-[2-(tert-Butyl)-6-methoxy-8-quinolylamino]pentyl}-(2S/2R)-2-aminosubstitutedamides (21-33) and N1-[4-(4-ethyl-6-methoxy-5-pentyloxy-8-quinolylamino)pentyl]-(2S/2R)-2-aminosubstitutedamides (51-63) were synthesized in six steps from 6-methoxy-8-nitroquinoline and 4-methoxy-2-nitro-5-pentyloxyaniline, respectively. Several analogs displayed promising antimalarial activity in vitro against Plasmodium falciparum D6 (chloroquine-sensitive) and W2 (chloroquine-resistant) clones with high selectivity indices versus mammalian cells. The most promising analogs (21-24) also displayed potent antimalarial activity in vivo in a Plasmodium berghei-infected mouse model. Most interestingly, many analogs exhibited promising in vitro antileishmanial activity against Leishmania donovani promastigotes, and antimicrobial activities against a panel of pathogenic bacteria and fungi. Several analogs, notably 21-24, 26-32, and 60, showed less MetHb formation compared to primaquine indicating the potential of these compounds in 8-quinolinamine-based antimalarial drug development.
|
Antileishmanial activity against Leishmania donovani promastigotes by Alamar blue assay
|
Leishmania donovani
|
19.9
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, antimalarial, antileishmanial, antimicrobial, cytotoxicity, and methemoglobin (MetHB) formation activities of new 8-quinolinamines.
Year : 2007
Volume : 15
Issue : 2
First Page : 915
Last Page : 930
Authors : Kaur K, Patel SR, Patil P, Jain M, Khan SI, Jacob MR, Ganesan S, Tekwani BL, Jain R.
Abstract : We report the synthesis, in vitro antiprotozoal (against Plasmodium and Leishmania), antimicrobial, cytotoxicity (Vero and MetHb-producing properties), and in vivo antimalarial activities of two series of 8-quinolinamines. N1-{4-[2-(tert-Butyl)-6-methoxy-8-quinolylamino]pentyl}-(2S/2R)-2-aminosubstitutedamides (21-33) and N1-[4-(4-ethyl-6-methoxy-5-pentyloxy-8-quinolylamino)pentyl]-(2S/2R)-2-aminosubstitutedamides (51-63) were synthesized in six steps from 6-methoxy-8-nitroquinoline and 4-methoxy-2-nitro-5-pentyloxyaniline, respectively. Several analogs displayed promising antimalarial activity in vitro against Plasmodium falciparum D6 (chloroquine-sensitive) and W2 (chloroquine-resistant) clones with high selectivity indices versus mammalian cells. The most promising analogs (21-24) also displayed potent antimalarial activity in vivo in a Plasmodium berghei-infected mouse model. Most interestingly, many analogs exhibited promising in vitro antileishmanial activity against Leishmania donovani promastigotes, and antimicrobial activities against a panel of pathogenic bacteria and fungi. Several analogs, notably 21-24, 26-32, and 60, showed less MetHb formation compared to primaquine indicating the potential of these compounds in 8-quinolinamine-based antimalarial drug development.
|
Induction of lysosomal disruption in Wistar rat hepatocytes assessed as beta-glucuronidase associated glycoprotein levels at 50 uM by immunoblot
|
Rattus norvegicus
|
1.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Primaquine revisited six decades after its discovery.
Year : 2009
Volume : 44
Issue : 3
First Page : 937
Last Page : 953
Authors : Vale N, Moreira R, Gomes P.
Abstract : Primaquine was firstly synthesized in 1946 in the USA, and is the most representative member of the anti-malarial 8-aminoquinolines. Six decades have passed and primaquine is still the only transmission-blocking anti-malarial clinically available, displaying a marked activity against gametocytes of all species of human malaria, including multi-resistant Plasmodium falciparum strains. Primaquine is also effective against all exoerythrocytic forms of the parasite and is used in conjunction with other anti-malarials for the treatment of vivax and ovale malaria. However, primaquine is often associated with serious adverse effects, in consequence of its toxic metabolites. 5-Hydroxyprimaquine or 6-methoxy-8-aminoquinoline has been considered to be directly responsible for complications such as hemolytic anemia. Primaquine toxicity is aggravated in people deficient of 6-glucose phosphate dehydrogenase or glutathione synthetase. Adverse effects are further amplified by the fact that primaquine must be repeatedly administered at high doses, due to its limited oral bioavailability. Over the last two decades, Medicinal Chemists have battled against primaquine's disadvantages, while keeping or even improving its unequalled performance as an anti-malarial. The present text revisits primaquine and its properties on the occasion of its 60th anniversary and aims to give a general overview of what has been the path towards the development of effective and safe primaquine-based anti-malarials. Presently, aablaquine and tafenoquine the two most promising primaquine analogues are already in the final stages of clinical trials against Plasmodium vivax and P. falciparum. Both compounds are a new hope against malaria and other primaquine-sensitive illnesses, such as Pneumocystis Pneumonia or the Chagas disease.
|
Induction of lysosomal disruption in Wistar rat hepatocytes assessed as beta-glucuronidase associated glycoprotein levels at 100 uM by immunoblot
|
Rattus norvegicus
|
4.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Primaquine revisited six decades after its discovery.
Year : 2009
Volume : 44
Issue : 3
First Page : 937
Last Page : 953
Authors : Vale N, Moreira R, Gomes P.
Abstract : Primaquine was firstly synthesized in 1946 in the USA, and is the most representative member of the anti-malarial 8-aminoquinolines. Six decades have passed and primaquine is still the only transmission-blocking anti-malarial clinically available, displaying a marked activity against gametocytes of all species of human malaria, including multi-resistant Plasmodium falciparum strains. Primaquine is also effective against all exoerythrocytic forms of the parasite and is used in conjunction with other anti-malarials for the treatment of vivax and ovale malaria. However, primaquine is often associated with serious adverse effects, in consequence of its toxic metabolites. 5-Hydroxyprimaquine or 6-methoxy-8-aminoquinoline has been considered to be directly responsible for complications such as hemolytic anemia. Primaquine toxicity is aggravated in people deficient of 6-glucose phosphate dehydrogenase or glutathione synthetase. Adverse effects are further amplified by the fact that primaquine must be repeatedly administered at high doses, due to its limited oral bioavailability. Over the last two decades, Medicinal Chemists have battled against primaquine's disadvantages, while keeping or even improving its unequalled performance as an anti-malarial. The present text revisits primaquine and its properties on the occasion of its 60th anniversary and aims to give a general overview of what has been the path towards the development of effective and safe primaquine-based anti-malarials. Presently, aablaquine and tafenoquine the two most promising primaquine analogues are already in the final stages of clinical trials against Plasmodium vivax and P. falciparum. Both compounds are a new hope against malaria and other primaquine-sensitive illnesses, such as Pneumocystis Pneumonia or the Chagas disease.
|
Induction of lysosomal disruption in Wistar rat homogenized hepatocytes assessed as beta-glucuronidase associated glycoprotein levels at 50 uM by immunoblot
|
Rattus norvegicus
|
2.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Primaquine revisited six decades after its discovery.
Year : 2009
Volume : 44
Issue : 3
First Page : 937
Last Page : 953
Authors : Vale N, Moreira R, Gomes P.
Abstract : Primaquine was firstly synthesized in 1946 in the USA, and is the most representative member of the anti-malarial 8-aminoquinolines. Six decades have passed and primaquine is still the only transmission-blocking anti-malarial clinically available, displaying a marked activity against gametocytes of all species of human malaria, including multi-resistant Plasmodium falciparum strains. Primaquine is also effective against all exoerythrocytic forms of the parasite and is used in conjunction with other anti-malarials for the treatment of vivax and ovale malaria. However, primaquine is often associated with serious adverse effects, in consequence of its toxic metabolites. 5-Hydroxyprimaquine or 6-methoxy-8-aminoquinoline has been considered to be directly responsible for complications such as hemolytic anemia. Primaquine toxicity is aggravated in people deficient of 6-glucose phosphate dehydrogenase or glutathione synthetase. Adverse effects are further amplified by the fact that primaquine must be repeatedly administered at high doses, due to its limited oral bioavailability. Over the last two decades, Medicinal Chemists have battled against primaquine's disadvantages, while keeping or even improving its unequalled performance as an anti-malarial. The present text revisits primaquine and its properties on the occasion of its 60th anniversary and aims to give a general overview of what has been the path towards the development of effective and safe primaquine-based anti-malarials. Presently, aablaquine and tafenoquine the two most promising primaquine analogues are already in the final stages of clinical trials against Plasmodium vivax and P. falciparum. Both compounds are a new hope against malaria and other primaquine-sensitive illnesses, such as Pneumocystis Pneumonia or the Chagas disease.
|
Induction of lysosomal disruption in Wistar rat homogenized hepatocytes assessed as beta-glucuronidase associated glycoprotein levels at 100 uM by immunoblot
|
Rattus norvegicus
|
7.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Primaquine revisited six decades after its discovery.
Year : 2009
Volume : 44
Issue : 3
First Page : 937
Last Page : 953
Authors : Vale N, Moreira R, Gomes P.
Abstract : Primaquine was firstly synthesized in 1946 in the USA, and is the most representative member of the anti-malarial 8-aminoquinolines. Six decades have passed and primaquine is still the only transmission-blocking anti-malarial clinically available, displaying a marked activity against gametocytes of all species of human malaria, including multi-resistant Plasmodium falciparum strains. Primaquine is also effective against all exoerythrocytic forms of the parasite and is used in conjunction with other anti-malarials for the treatment of vivax and ovale malaria. However, primaquine is often associated with serious adverse effects, in consequence of its toxic metabolites. 5-Hydroxyprimaquine or 6-methoxy-8-aminoquinoline has been considered to be directly responsible for complications such as hemolytic anemia. Primaquine toxicity is aggravated in people deficient of 6-glucose phosphate dehydrogenase or glutathione synthetase. Adverse effects are further amplified by the fact that primaquine must be repeatedly administered at high doses, due to its limited oral bioavailability. Over the last two decades, Medicinal Chemists have battled against primaquine's disadvantages, while keeping or even improving its unequalled performance as an anti-malarial. The present text revisits primaquine and its properties on the occasion of its 60th anniversary and aims to give a general overview of what has been the path towards the development of effective and safe primaquine-based anti-malarials. Presently, aablaquine and tafenoquine the two most promising primaquine analogues are already in the final stages of clinical trials against Plasmodium vivax and P. falciparum. Both compounds are a new hope against malaria and other primaquine-sensitive illnesses, such as Pneumocystis Pneumonia or the Chagas disease.
|
Antimalarial activity against Plasmodium yoelii 265 sporozoites in primary mice (Mus musculus) hepatocytes after 48 hrs
|
Plasmodium yoelii yoelii
|
640.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Isolation and antimalarial activity of new morphinan alkaloids on Plasmodium yoelii liver stage.
Year : 2008
Volume : 16
Issue : 11
First Page : 6186
Last Page : 6192
Authors : Carraz M, Jossang A, Rasoanaivo P, Mazier D, Frappier F.
Abstract : Decoction of Strychnopsis thouarsii is used in the Malagasy traditional medicine to combat malaria. We have shown that this traditional remedy prevents malaria infection by targeting Plasmodium at its early liver stage. Bioassay-guided fractionation of S. thouarsii stem barks extracts, using a rodent Plasmodium yoelii liver stage parasites inhibition assay, led to isolate the new morphinan alkaloid tazopsine (1) together with sinococuline (2) and two other new related morphinan analogs, 10-epi-tazopsine (3) and 10-epi-tazoside (4). Structures were characterized by 2D NMR, MS, and CD spectral analysis. Compounds 1-3 were found to fully inhibit the rodent P. yoelii liver stage parasites in vitro.
|
Antimalarial activity against Plasmodium yoelii 265 BY liver stage sporozoites in primary mice (Mus musculus) hepatocytes at 38.6 uM after 48 hrs
|
Plasmodium yoelii yoelii
|
80.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Isolation and antimalarial activity of new morphinan alkaloids on Plasmodium yoelii liver stage.
Year : 2008
Volume : 16
Issue : 11
First Page : 6186
Last Page : 6192
Authors : Carraz M, Jossang A, Rasoanaivo P, Mazier D, Frappier F.
Abstract : Decoction of Strychnopsis thouarsii is used in the Malagasy traditional medicine to combat malaria. We have shown that this traditional remedy prevents malaria infection by targeting Plasmodium at its early liver stage. Bioassay-guided fractionation of S. thouarsii stem barks extracts, using a rodent Plasmodium yoelii liver stage parasites inhibition assay, led to isolate the new morphinan alkaloid tazopsine (1) together with sinococuline (2) and two other new related morphinan analogs, 10-epi-tazopsine (3) and 10-epi-tazoside (4). Structures were characterized by 2D NMR, MS, and CD spectral analysis. Compounds 1-3 were found to fully inhibit the rodent P. yoelii liver stage parasites in vitro.
|
Antiproliferative activity against human MCF7 cells at 100 uM after 24 hrs
|
Homo sapiens
|
20.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Urea and carbamate derivatives of primaquine: synthesis, cytostatic and antioxidant activities.
Year : 2009
Volume : 17
Issue : 15
First Page : 5605
Last Page : 5613
Authors : Simunović M, Perković I, Zorc B, Ester K, Kralj M, Hadjipavlou-Litina D, Pontiki E.
Abstract : The novel urea primaquine derivatives 3 were prepared by aminolysis of primaquine benzotriazolide 2 with several hydroxyamines and ethylendiamine, while carbamates 4 were synthesized from the same precursor 2 and alcohols. All compounds are fully chemically characterized and evaluated for their cytostatic and antioxidant activities. The most prominent antiproliferative activity was obtained by compounds 3c, 3d, 3g, and 5b (IC(50)=9-40 microM). 1-(5-Hydroxypentyl)-3-[4-(6-methoxy-quinolin-8-ylamino)-pentyl]urea (3c) showed extreme selectivity toward SW 620 colon cancer cells (IC(50)=0.2 microM) and a bit less toward lung cancer cells H 460. Hydroxyurea 3h showed the highest interaction with DPPH. Primaquine twin drug 3g showed very significant inhibition on LOX soybean (IC(50)=62 microM). Almost all the tested derivatives highly inhibited lipid peroxidation, significantly stronger than primaquine phosphate.
|
Antioxidant activity assessed as inhibition of AAPH-induced lipid peroxidation at 0.1 mM
|
None
|
45.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Urea and carbamate derivatives of primaquine: synthesis, cytostatic and antioxidant activities.
Year : 2009
Volume : 17
Issue : 15
First Page : 5605
Last Page : 5613
Authors : Simunović M, Perković I, Zorc B, Ester K, Kralj M, Hadjipavlou-Litina D, Pontiki E.
Abstract : The novel urea primaquine derivatives 3 were prepared by aminolysis of primaquine benzotriazolide 2 with several hydroxyamines and ethylendiamine, while carbamates 4 were synthesized from the same precursor 2 and alcohols. All compounds are fully chemically characterized and evaluated for their cytostatic and antioxidant activities. The most prominent antiproliferative activity was obtained by compounds 3c, 3d, 3g, and 5b (IC(50)=9-40 microM). 1-(5-Hydroxypentyl)-3-[4-(6-methoxy-quinolin-8-ylamino)-pentyl]urea (3c) showed extreme selectivity toward SW 620 colon cancer cells (IC(50)=0.2 microM) and a bit less toward lung cancer cells H 460. Hydroxyurea 3h showed the highest interaction with DPPH. Primaquine twin drug 3g showed very significant inhibition on LOX soybean (IC(50)=62 microM). Almost all the tested derivatives highly inhibited lipid peroxidation, significantly stronger than primaquine phosphate.
|
Antimicrobial activity against Plasmodium yoelii 265 liver infected in mammalian hepatocytes after 48 hrs
|
Plasmodium yoelii yoelii
|
75.7
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : New active drugs against liver stages of Plasmodium predicted by molecular topology.
Year : 2008
Volume : 52
Issue : 4
First Page : 1215
Last Page : 1220
Authors : Mahmoudi N, Garcia-Domenech R, Galvez J, Farhati K, Franetich JF, Sauerwein R, Hannoun L, Derouin F, Danis M, Mazier D.
Abstract : We conducted a quantitative structure-activity relationship (QSAR) study based on a database of 127 compounds previously tested against the liver stage of Plasmodium yoelii in order to develop a model capable of predicting the in vitro antimalarial activities of new compounds. Topological indices were used as structural descriptors, and their relation to antimalarial activity was determined by using linear discriminant analysis. A topological model consisting of two discriminant functions was created. The first function discriminated between active and inactive compounds, and the second identified the most active among the active compounds. The model was then applied sequentially to a large database of compounds with unknown activity against liver stages of Plasmodium. Seventeen drugs that were predicted to be active or inactive were selected for testing against the hepatic stage of P. yoelii in vitro. Antiretroviral, antifungal, and cardiotonic drugs were found to be highly active (nanomolar 50% inhibitory concentration values), and two ionophores completely inhibited parasite development. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed on hepatocyte cultures for all compounds, and none of these compounds were toxic in vitro. For both ionophores, the same in vitro assay as those for P. yoelii has confirmed their in vitro activities on Plasmodium falciparum. A similar topological model was used to estimate the octanol/water partition of each compound. These results demonstrate the utility of the QSAR and molecular topology approaches for identifying new drugs that are active against the hepatic stage of malaria parasites. We also show the remarkable efficacy of some drugs that were not previously reported to have antiparasitic activity.
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum D6 by LDH assay
|
Plasmodium falciparum
|
2.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, antiprotozoal, antimicrobial, β-hematin inhibition, cytotoxicity and methemoglobin (MetHb) formation activities of bis(8-aminoquinolines).
Year : 2011
Volume : 19
Issue : 1
First Page : 197
Last Page : 210
Authors : Kaur K, Jain M, Khan SI, Jacob MR, Tekwani BL, Singh S, Singh PP, Jain R.
Abstract : In continuing our search of potent antimalarials based on 8-aminoquinoline structural framework, three series of novel bis(8-aminoquinolines) using convenient one to four steps synthetic procedures were synthesized. The bisquinolines were evaluated for in vitro antimalarial (Plasmodiumfalciparum), antileishmanial (Leishmaniadonovani), antimicrobial (a panel of pathogenic bacteria and fungi), cytotoxicity, β-hematin inhibitory and methemoglobin (MetHb) formation activities. Several compounds exhibited superior antimalarial activities compared to parent drug primaquine. Selected compounds (44, 61 and 79) when tested for in vivo blood-schizontocidal antimalarial activity (Plasmodiumberghei) displayed potent blood-schizontocial activities. The bisquinolines showed negligible MetHb formation (0.2-1.2%) underlining their potential in the treatment of glucose-6-phosphate dehydrogenase deficient patients. The bisquinoline analogues (36, 73 and 79) also exhibited promising in vitro antileishmanial activity, and antimicrobial activities (43, 44 and 76) against a panel of pathogenic bacteria and fungi. The results of this study provide evidence that bis(8-aminoquinolines), like their bis(4-aminoquinolines) and artemisinin dimers counterparts, are a promising class of antimalarial agents.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum W2 by LDH assay
|
Plasmodium falciparum
|
2.8
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, antiprotozoal, antimicrobial, β-hematin inhibition, cytotoxicity and methemoglobin (MetHb) formation activities of bis(8-aminoquinolines).
Year : 2011
Volume : 19
Issue : 1
First Page : 197
Last Page : 210
Authors : Kaur K, Jain M, Khan SI, Jacob MR, Tekwani BL, Singh S, Singh PP, Jain R.
Abstract : In continuing our search of potent antimalarials based on 8-aminoquinoline structural framework, three series of novel bis(8-aminoquinolines) using convenient one to four steps synthetic procedures were synthesized. The bisquinolines were evaluated for in vitro antimalarial (Plasmodiumfalciparum), antileishmanial (Leishmaniadonovani), antimicrobial (a panel of pathogenic bacteria and fungi), cytotoxicity, β-hematin inhibitory and methemoglobin (MetHb) formation activities. Several compounds exhibited superior antimalarial activities compared to parent drug primaquine. Selected compounds (44, 61 and 79) when tested for in vivo blood-schizontocidal antimalarial activity (Plasmodiumberghei) displayed potent blood-schizontocial activities. The bisquinolines showed negligible MetHb formation (0.2-1.2%) underlining their potential in the treatment of glucose-6-phosphate dehydrogenase deficient patients. The bisquinoline analogues (36, 73 and 79) also exhibited promising in vitro antileishmanial activity, and antimicrobial activities (43, 44 and 76) against a panel of pathogenic bacteria and fungi. The results of this study provide evidence that bis(8-aminoquinolines), like their bis(4-aminoquinolines) and artemisinin dimers counterparts, are a promising class of antimalarial agents.
|
Antileishmanial activity against promastigotes of Leishmania donovani by alamar blue assay
|
Leishmania donovani
|
19.9
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, antiprotozoal, antimicrobial, β-hematin inhibition, cytotoxicity and methemoglobin (MetHb) formation activities of bis(8-aminoquinolines).
Year : 2011
Volume : 19
Issue : 1
First Page : 197
Last Page : 210
Authors : Kaur K, Jain M, Khan SI, Jacob MR, Tekwani BL, Singh S, Singh PP, Jain R.
Abstract : In continuing our search of potent antimalarials based on 8-aminoquinoline structural framework, three series of novel bis(8-aminoquinolines) using convenient one to four steps synthetic procedures were synthesized. The bisquinolines were evaluated for in vitro antimalarial (Plasmodiumfalciparum), antileishmanial (Leishmaniadonovani), antimicrobial (a panel of pathogenic bacteria and fungi), cytotoxicity, β-hematin inhibitory and methemoglobin (MetHb) formation activities. Several compounds exhibited superior antimalarial activities compared to parent drug primaquine. Selected compounds (44, 61 and 79) when tested for in vivo blood-schizontocidal antimalarial activity (Plasmodiumberghei) displayed potent blood-schizontocial activities. The bisquinolines showed negligible MetHb formation (0.2-1.2%) underlining their potential in the treatment of glucose-6-phosphate dehydrogenase deficient patients. The bisquinoline analogues (36, 73 and 79) also exhibited promising in vitro antileishmanial activity, and antimicrobial activities (43, 44 and 76) against a panel of pathogenic bacteria and fungi. The results of this study provide evidence that bis(8-aminoquinolines), like their bis(4-aminoquinolines) and artemisinin dimers counterparts, are a promising class of antimalarial agents.
|
Antimalarial activity against mefloquine-resistant Plasmodium falciparum CDC Sierra Leone 1 D6 after 48 hrs by [3H]hypoxanthine uptake assay
|
Plasmodium falciparum
|
2.1
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives.
Year : 2011
Volume : 54
Issue : 1
First Page : 131
Last Page : 142
Authors : Shiraki H, Kozar MP, Melendez V, Hudson TH, Ohrt C, Magill AJ, Lin AJ.
Abstract : In an attempt to separate the antimalarial activity of tafenoquine (3) from its hemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficiency patients, a series of 5-aryl-8-aminoquinoline derivatives was prepared and assessed for antimalarial activities. The new compounds were found metabolically stable in human and mouse microsomal preparations, with t(1/2) > 60 min, and were equal to or more potent than primaquine (2) and 3 against Plasmodium falciparum cell growth. The new agents were more active against the chloroquine (CQ) resistant clone than to the CQ-sensitive clone. Analogues with electron donating groups showed better activity than those with electron withdrawing substituents. Compounds 4bc, 4bd, and 4be showed comparable therapeutic index (TI) to that of 2 and 3, with TI ranging from 5 to 8 based on IC(50) data. The new compounds showed no significant causal prophylactic activity in mice infected with Plasmodium berghei sporozoites, but are substantially less toxic than 2 and 3 in mouse tests.
|
Antimalarial activity against mefloquine-susceptible Plasmodium falciparum CDC Indochina 3 W2 after 48 hrs by [3H]hypoxanthine uptake assay
|
Plasmodium falciparum
|
0.9
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives.
Year : 2011
Volume : 54
Issue : 1
First Page : 131
Last Page : 142
Authors : Shiraki H, Kozar MP, Melendez V, Hudson TH, Ohrt C, Magill AJ, Lin AJ.
Abstract : In an attempt to separate the antimalarial activity of tafenoquine (3) from its hemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficiency patients, a series of 5-aryl-8-aminoquinoline derivatives was prepared and assessed for antimalarial activities. The new compounds were found metabolically stable in human and mouse microsomal preparations, with t(1/2) > 60 min, and were equal to or more potent than primaquine (2) and 3 against Plasmodium falciparum cell growth. The new agents were more active against the chloroquine (CQ) resistant clone than to the CQ-sensitive clone. Analogues with electron donating groups showed better activity than those with electron withdrawing substituents. Compounds 4bc, 4bd, and 4be showed comparable therapeutic index (TI) to that of 2 and 3, with TI ranging from 5 to 8 based on IC(50) data. The new compounds showed no significant causal prophylactic activity in mice infected with Plasmodium berghei sporozoites, but are substantially less toxic than 2 and 3 in mouse tests.
|
Cytotoxicity against mouse RAW264.7 cells after 24 hrs by MTT assay
|
Mus musculus
|
38.7
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives.
Year : 2011
Volume : 54
Issue : 1
First Page : 131
Last Page : 142
Authors : Shiraki H, Kozar MP, Melendez V, Hudson TH, Ohrt C, Magill AJ, Lin AJ.
Abstract : In an attempt to separate the antimalarial activity of tafenoquine (3) from its hemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficiency patients, a series of 5-aryl-8-aminoquinoline derivatives was prepared and assessed for antimalarial activities. The new compounds were found metabolically stable in human and mouse microsomal preparations, with t(1/2) > 60 min, and were equal to or more potent than primaquine (2) and 3 against Plasmodium falciparum cell growth. The new agents were more active against the chloroquine (CQ) resistant clone than to the CQ-sensitive clone. Analogues with electron donating groups showed better activity than those with electron withdrawing substituents. Compounds 4bc, 4bd, and 4be showed comparable therapeutic index (TI) to that of 2 and 3, with TI ranging from 5 to 8 based on IC(50) data. The new compounds showed no significant causal prophylactic activity in mice infected with Plasmodium berghei sporozoites, but are substantially less toxic than 2 and 3 in mouse tests.
|
Antiplasmodial activity against multidrug-resistant Plasmodium falciparum VS/1 by [3H]hypoxanthine incorporation assay
|
Plasmodium falciparum VS/1
|
326.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro chemosensitization of Plasmodium falciparum to antimalarials by verapamil and probenecid.
Year : 2009
Volume : 53
Issue : 7
First Page : 3131
Last Page : 3134
Authors : Masseno V, Muriithi S, Nzila A.
Abstract : We tested the effect of probenecid and verapamil in chemosensitizing Plasmodium falciparum to 14 antimalarials using the multidrug-resistant strain V1S and the drug-sensitive 3D7. Verapamil chemosensitizes V1S to quinine and chloroquine. Interestingly, probenecid profoundly chemosensitizes V1S to piperaquine. Thus, probenecid could be used to increase piperaquine efficacy in vivo.
|
Antiplasmodial activity against Plasmodium falciparum 3D7 by [3H]hypoxanthine incorporation assay
|
Plasmodium falciparum
|
326.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro chemosensitization of Plasmodium falciparum to antimalarials by verapamil and probenecid.
Year : 2009
Volume : 53
Issue : 7
First Page : 3131
Last Page : 3134
Authors : Masseno V, Muriithi S, Nzila A.
Abstract : We tested the effect of probenecid and verapamil in chemosensitizing Plasmodium falciparum to 14 antimalarials using the multidrug-resistant strain V1S and the drug-sensitive 3D7. Verapamil chemosensitizes V1S to quinine and chloroquine. Interestingly, probenecid profoundly chemosensitizes V1S to piperaquine. Thus, probenecid could be used to increase piperaquine efficacy in vivo.
|
Antiplasmodial activity against Plasmodium falciparum F32 assessed as suppression of parasitemia after 4 hrs by Giemsa staining
|
Plasmodium falciparum
|
6.17
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Antimalarial activity of simalikalactone E, a new quassinoid from Quassia amara L. (Simaroubaceae).
Year : 2009
Volume : 53
Issue : 10
First Page : 4393
Last Page : 4398
Authors : Cachet N, Hoakwie F, Bertani S, Bourdy G, Deharo E, Stien D, Houel E, Gornitzka H, Fillaux J, Chevalley S, Valentin A, Jullian V.
Abstract : We report the isolation and identification of a new quassinoid named simalikalactone E (SkE), extracted from a widely used Amazonian antimalarial remedy made out of Quassia amara L. (Simaroubaceae) leaves. This new molecule inhibited the growth of Plasmodium falciparum cultured in vitro by 50%, in the concentration range from 24 to 68 nM, independently of the strain sensitivity to chloroquine. We also showed that this compound was able to decrease gametocytemia with a 50% inhibitory concentration sevenfold lower than that of primaquine. SkE was found to be less toxic than simalikalactone D (SkD), another antimalarial quassinoid from Q. amara, and its cytotoxicity on mammalian cells was dependent on the cell line, displaying a good selectivity index when tested on nontumorogenic cells. In vivo, SkE inhibited murine malaria growth of Plasmodium vinckei petteri by 50% at 1 and 0.5 mg/kg of body weight/day, by the oral or intraperitoneal routes, respectively. The contribution of quassinoids as a source of antimalarial molecules needs therefore to be reconsidered.
|
Antiplasmodial activity against Plasmodium falciparum FcB1/Columbia assessed as suppression of parasitemia after 4 hrs by Giemsa staining
|
Plasmodium falciparum FcB1/Columbia
|
8.9
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Antimalarial activity of simalikalactone E, a new quassinoid from Quassia amara L. (Simaroubaceae).
Year : 2009
Volume : 53
Issue : 10
First Page : 4393
Last Page : 4398
Authors : Cachet N, Hoakwie F, Bertani S, Bourdy G, Deharo E, Stien D, Houel E, Gornitzka H, Fillaux J, Chevalley S, Valentin A, Jullian V.
Abstract : We report the isolation and identification of a new quassinoid named simalikalactone E (SkE), extracted from a widely used Amazonian antimalarial remedy made out of Quassia amara L. (Simaroubaceae) leaves. This new molecule inhibited the growth of Plasmodium falciparum cultured in vitro by 50%, in the concentration range from 24 to 68 nM, independently of the strain sensitivity to chloroquine. We also showed that this compound was able to decrease gametocytemia with a 50% inhibitory concentration sevenfold lower than that of primaquine. SkE was found to be less toxic than simalikalactone D (SkD), another antimalarial quassinoid from Q. amara, and its cytotoxicity on mammalian cells was dependent on the cell line, displaying a good selectivity index when tested on nontumorogenic cells. In vivo, SkE inhibited murine malaria growth of Plasmodium vinckei petteri by 50% at 1 and 0.5 mg/kg of body weight/day, by the oral or intraperitoneal routes, respectively. The contribution of quassinoids as a source of antimalarial molecules needs therefore to be reconsidered.
|
Antiplasmodial activity against Plasmodium falciparum W2 assessed as suppression of parasitemia after 4 hrs by Giemsa staining
|
Plasmodium falciparum
|
7.14
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Antimalarial activity of simalikalactone E, a new quassinoid from Quassia amara L. (Simaroubaceae).
Year : 2009
Volume : 53
Issue : 10
First Page : 4393
Last Page : 4398
Authors : Cachet N, Hoakwie F, Bertani S, Bourdy G, Deharo E, Stien D, Houel E, Gornitzka H, Fillaux J, Chevalley S, Valentin A, Jullian V.
Abstract : We report the isolation and identification of a new quassinoid named simalikalactone E (SkE), extracted from a widely used Amazonian antimalarial remedy made out of Quassia amara L. (Simaroubaceae) leaves. This new molecule inhibited the growth of Plasmodium falciparum cultured in vitro by 50%, in the concentration range from 24 to 68 nM, independently of the strain sensitivity to chloroquine. We also showed that this compound was able to decrease gametocytemia with a 50% inhibitory concentration sevenfold lower than that of primaquine. SkE was found to be less toxic than simalikalactone D (SkD), another antimalarial quassinoid from Q. amara, and its cytotoxicity on mammalian cells was dependent on the cell line, displaying a good selectivity index when tested on nontumorogenic cells. In vivo, SkE inhibited murine malaria growth of Plasmodium vinckei petteri by 50% at 1 and 0.5 mg/kg of body weight/day, by the oral or intraperitoneal routes, respectively. The contribution of quassinoids as a source of antimalarial molecules needs therefore to be reconsidered.
|
Antiplasmodial activity against Plasmodium falciparum W2 gametocytes assessed as suppression of parasitemia after 4 hrs by Giemsa staining
|
Plasmodium falciparum
|
8.9
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Antimalarial activity of simalikalactone E, a new quassinoid from Quassia amara L. (Simaroubaceae).
Year : 2009
Volume : 53
Issue : 10
First Page : 4393
Last Page : 4398
Authors : Cachet N, Hoakwie F, Bertani S, Bourdy G, Deharo E, Stien D, Houel E, Gornitzka H, Fillaux J, Chevalley S, Valentin A, Jullian V.
Abstract : We report the isolation and identification of a new quassinoid named simalikalactone E (SkE), extracted from a widely used Amazonian antimalarial remedy made out of Quassia amara L. (Simaroubaceae) leaves. This new molecule inhibited the growth of Plasmodium falciparum cultured in vitro by 50%, in the concentration range from 24 to 68 nM, independently of the strain sensitivity to chloroquine. We also showed that this compound was able to decrease gametocytemia with a 50% inhibitory concentration sevenfold lower than that of primaquine. SkE was found to be less toxic than simalikalactone D (SkD), another antimalarial quassinoid from Q. amara, and its cytotoxicity on mammalian cells was dependent on the cell line, displaying a good selectivity index when tested on nontumorogenic cells. In vivo, SkE inhibited murine malaria growth of Plasmodium vinckei petteri by 50% at 1 and 0.5 mg/kg of body weight/day, by the oral or intraperitoneal routes, respectively. The contribution of quassinoids as a source of antimalarial molecules needs therefore to be reconsidered.
|
DRUGMATRIX: Transporter, Serotonin (5-Hydroxytryptamine) (SERT) radioligand binding (ligand: [3H] Paroxetine)
|
None
|
16.0
nM
|
|
DRUGMATRIX: Transporter, Serotonin (5-Hydroxytryptamine) (SERT) radioligand binding (ligand: [3H] Paroxetine)
|
None
|
8.405
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: CYP450, 1A2 enzyme inhibition (substrate: 3-Cyano-7-ethoxycoumarin)
|
None
|
182.4
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum D6 assessed as plasmodial LDH activity
|
Plasmodium falciparum
|
2.0
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Amino acid, dipeptide and pseudodipeptide conjugates of ring-substituted 8-aminoquinolines: synthesis and evaluation of anti-infective, β-haematin inhibition and cytotoxic activities.
Year : 2012
Volume : 52
First Page : 230
Last Page : 241
Authors : Kaur K, Jain M, Khan SI, Jacob MR, Tekwani BL, Singh S, Singh PP, Jain R.
Abstract : Three new series of 8-aminoquinolines with modifications in the side-chain by conjugation with amino acids, dipeptides and pseudodipeptides have been synthesized. The synthesized compounds were tested for in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, in vitro cytotoxicity in mammalian kidney cells (Vero), in vitro antileishmanial activity against Leishmania donovani, in vitro antimicrobial activity and in vitro inhibition of β-haematin formation. The promising compounds were also evaluated for in vivo blood-schizontocidal antimalarial activity against Plasmodium berghei infected mice. The analogues 55 and 101 produced highest antimalarial activities, in vitro. Analogues 52 and 59 exhibited promising antileishmanial and broad spectrum of antifungal activities, respectively.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum W2 assessed as plasmodial LDH activity
|
Plasmodium falciparum
|
2.8
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Amino acid, dipeptide and pseudodipeptide conjugates of ring-substituted 8-aminoquinolines: synthesis and evaluation of anti-infective, β-haematin inhibition and cytotoxic activities.
Year : 2012
Volume : 52
First Page : 230
Last Page : 241
Authors : Kaur K, Jain M, Khan SI, Jacob MR, Tekwani BL, Singh S, Singh PP, Jain R.
Abstract : Three new series of 8-aminoquinolines with modifications in the side-chain by conjugation with amino acids, dipeptides and pseudodipeptides have been synthesized. The synthesized compounds were tested for in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, in vitro cytotoxicity in mammalian kidney cells (Vero), in vitro antileishmanial activity against Leishmania donovani, in vitro antimicrobial activity and in vitro inhibition of β-haematin formation. The promising compounds were also evaluated for in vivo blood-schizontocidal antimalarial activity against Plasmodium berghei infected mice. The analogues 55 and 101 produced highest antimalarial activities, in vitro. Analogues 52 and 59 exhibited promising antileishmanial and broad spectrum of antifungal activities, respectively.
|
Antileishmanial activity against Leishmania donovani promastigote by by Alamar Blue assay
|
Leishmania donovani
|
19.9
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Amino acid, dipeptide and pseudodipeptide conjugates of ring-substituted 8-aminoquinolines: synthesis and evaluation of anti-infective, β-haematin inhibition and cytotoxic activities.
Year : 2012
Volume : 52
First Page : 230
Last Page : 241
Authors : Kaur K, Jain M, Khan SI, Jacob MR, Tekwani BL, Singh S, Singh PP, Jain R.
Abstract : Three new series of 8-aminoquinolines with modifications in the side-chain by conjugation with amino acids, dipeptides and pseudodipeptides have been synthesized. The synthesized compounds were tested for in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, in vitro cytotoxicity in mammalian kidney cells (Vero), in vitro antileishmanial activity against Leishmania donovani, in vitro antimicrobial activity and in vitro inhibition of β-haematin formation. The promising compounds were also evaluated for in vivo blood-schizontocidal antimalarial activity against Plasmodium berghei infected mice. The analogues 55 and 101 produced highest antimalarial activities, in vitro. Analogues 52 and 59 exhibited promising antileishmanial and broad spectrum of antifungal activities, respectively.
|
Antimalarial activity against liver stages of Plasmodium yoelii yoelii
|
Plasmodium yoelii yoelii
|
75.7
nM
|
|
Journal : J. Med. Chem.
Title : Targeting the liver stage of malaria parasites: a yet unmet goal.
Year : 2012
Volume : 55
Issue : 3
First Page : 995
Last Page : 1012
Authors : Rodrigues T, Prudêncio M, Moreira R, Mota MM, Lopes F.
|
Antimalarial activity against liver stages of Plasmodium yoelii 265 BY infected in Swiss mouse after 48 hrs by fluorescence microscopy
|
Plasmodium yoelii
|
75.0
nM
|
|
Journal : J. Med. Chem.
Title : Targeting the liver stage of malaria parasites: a yet unmet goal.
Year : 2012
Volume : 55
Issue : 3
First Page : 995
Last Page : 1012
Authors : Rodrigues T, Prudêncio M, Moreira R, Mota MM, Lopes F.
|
Antimalarial activity against Plasmodium falciparum KT1 gametocytes
|
Plasmodium falciparum
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : Effects of antimalarial molecules on the gametocyte stage of Plasmodium falciparum: the debate.
Year : 2012
Volume : 55
Issue : 23
First Page : 10328
Last Page : 10344
Authors : Dechy-Cabaret O, Benoit-Vical F.
Abstract : Although the illness malaria is caused by the asexual blood stages, the presence of gametocytes is directly responsible for the infection of the vector Anopheles, thus perpetuating the plasmodial cycle. Fight against malaria is more than ever a current problem, and the solution will probably go through the development of efficient molecules against gametocytes. Knowledge of the pharmacological properties of antiplasmodials is helpful in term of using relevant molecules to treat malaria and to eradicate this dramatic public health problem. The effects of the major antiplasmodial drugs including artemisinin-based combination therapies on gametocyte load are thus reviewed herein, making the difference whenever possible between the effects on gametocytogenesis and the gametocytocidal activity. Current status on the portfolio of the most promising anti-gametocytes compounds is also presented. A close analysis of the relationship between chemical structure and antiplasmodial activity should help the design of novel antimalarial drugs targeting Plasmodium sexual stages.
|
Antimalarial activity against Plasmodium falciparum K1 assessed as inhibition of [3H] hypoxanthine uptake by liquid scintillation counting
|
Plasmodium falciparum K1
|
643.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Synthesis and antiplasmodial and antimycobacterial evaluation of new nitroimidazole and nitroimidazooxazine derivatives.
Year : 2013
Volume : 4
Issue : 1
First Page : 128
Last Page : 131
Authors : Tukulula M, Sharma RK, Meurillon M, Mahajan A, Naran K, Warner D, Huang J, Mekonnen B, Chibale K.
Abstract : The synthesis and antiplasmodial and antimycobacterial evaluation of two new series of nitroimidazole and nitroimidazooxazine derivatives is described. The majority of these compounds, especially hybrids 9d, 9f, and 14b, exhibited potent activity against the chloroquine-resistant K1 strain of Plasmodium falciparum. Furthermore, a notable number from the tetrazole series were significantly more active against M. tuberculosis than kanamycin, a standard TB drug.
|
Antimalarial activity against gametocytic stage of Plasmodium berghei infected in blood assessed as inhibition of ookinete formation at 10 uM after 24 hrs by Giemsa staining-based microscopic analysis relative to control
|
Plasmodium berghei
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Using genetic methods to define the targets of compounds with antimalarial activity.
Year : 2013
Volume : 56
Issue : 20
First Page : 7761
Last Page : 7771
Authors : Flannery EL, Fidock DA, Winzeler EA.
Abstract : Although phenotypic cellular screening has been used to drive antimalarial drug discovery in recent years, in some cases target-based drug discovery remains more attractive. This is especially true when appropriate high-throughput cellular assays are lacking, as is the case for drug discovery efforts that aim to provide a replacement for primaquine (4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine), the only drug that can block Plasmodium transmission to Anopheles mosquitoes and eliminate liver-stage hypnozoites. At present, however, there are no known chemically validated parasite protein targets that are important in all Plasmodium parasite developmental stages and that can be used in traditional biochemical compound screens. We propose that a plethora of novel, chemically validated, cross-stage antimalarial targets still remain to be discovered from the ~5,500 proteins encoded by the Plasmodium genomes. Here we discuss how in vitro evolution of drug-resistant strains of Plasmodium falciparum and subsequent whole-genome analysis can be used to find the targets of some of the many compounds discovered in whole-cell phenotypic screens.
|
Antimalarial activity against mature gametocytic stage of Plasmodium falciparum assessed as inhibition of mature gamete exflagellation at 10 uM incubated for 24 hrs prior to exflagellation induction at 21 degC measured after 20 mins by microscopic analysis relative to control
|
Plasmodium falciparum
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Using genetic methods to define the targets of compounds with antimalarial activity.
Year : 2013
Volume : 56
Issue : 20
First Page : 7761
Last Page : 7771
Authors : Flannery EL, Fidock DA, Winzeler EA.
Abstract : Although phenotypic cellular screening has been used to drive antimalarial drug discovery in recent years, in some cases target-based drug discovery remains more attractive. This is especially true when appropriate high-throughput cellular assays are lacking, as is the case for drug discovery efforts that aim to provide a replacement for primaquine (4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine), the only drug that can block Plasmodium transmission to Anopheles mosquitoes and eliminate liver-stage hypnozoites. At present, however, there are no known chemically validated parasite protein targets that are important in all Plasmodium parasite developmental stages and that can be used in traditional biochemical compound screens. We propose that a plethora of novel, chemically validated, cross-stage antimalarial targets still remain to be discovered from the ~5,500 proteins encoded by the Plasmodium genomes. Here we discuss how in vitro evolution of drug-resistant strains of Plasmodium falciparum and subsequent whole-genome analysis can be used to find the targets of some of the many compounds discovered in whole-cell phenotypic screens.
|
Antimalarial activity against late (4 to 5) gametocytic stage of Plasmodium falciparum at 120 uM after 72 hrs by image-based HTS assay relative to control
|
Plasmodium falciparum
|
40.0
%
|
|
Journal : J. Med. Chem.
Title : Approaches to protozoan drug discovery: phenotypic screening.
Year : 2013
Volume : 56
Issue : 20
First Page : 7727
Last Page : 7740
Authors : Sykes ML, Avery VM.
Abstract : Determining the activity of a compound and the potential impact on a diseased state is frequently undertaken using phenotypic or target-based approaches. Phenotypic screens have the advantage of the whole organism being exposed to the compound and thus all the targets and biological pathways associated with it. Cell penetration and access to targets in their "natural" environment are taken into account. Unless utilizing a genetically modified organism with an additional target associated indicator, elucidation of specific target(s) of active compounds is necessary. Target discovery is desirable to allow development of chemical entities based upon knowledge of the target structure. Phenotypic drug discovery has successfully identified new molecular entities for neglected protozoan disease research. In this perspective, the phenotypic approaches used to identify chemical entities for drug discovery and for use as tools against the parasites Plasmodium falciparum, Trypanosoma brucei brucei, and Trypanosoma cruzi will be outlined.
|
Antisporogonic activity against GFP expressing Plasmodium berghei ANKA infected in BALB/c mouse assessed as inhibition of appearance of oocysts in Anopheles gambiae level at 25 umol/kg, ip by microscopic analysis (Rvb = 83.6%)
|
Plasmodium berghei
|
2.2
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Novel endoperoxide-based transmission-blocking antimalarials with liver- and blood-schizontocidal activities.
Year : 2014
Volume : 5
Issue : 2
First Page : 108
Last Page : 112
Authors : Miranda D, Capela R, Albuquerque IS, Meireles P, Paiva I, Nogueira F, Amewu R, Gut J, Rosenthal PJ, Oliveira R, Mota MM, Moreira R, Marti F, Prudêncio M, O'Neill PM, Lopes F.
Abstract : In a search for effective compounds against both the blood- and liver-stages of infection by malaria parasites with the ability to block the transmission of the disease to mosquito vectors, a series of hybrid compounds combining either a 1,2,4-trioxane or 1,2,4,5-tetraoxane and 8-aminoquinoline moieties were synthesized and screened for their antimalarial activity. These hybrid compounds showed high potency against both exoerythrocytic and erythrocytic forms of malaria parasites, comparable to representative trioxane-based counterparts. Furthermore, they efficiently blocked the development of the sporogonic cycle in the mosquito vector. The tetraoxane-based hybrid 5, containing an amide linker between the two moieties, effectively cleared a patent blood-stage P. berghei infection in mice after i.p. administration. Overall, these results indicate that peroxide-8-aminoquinoline hybrids are excellent starting points to develop an agent that conveys all the desired antimalarial multistage activities in a single chemical entity and, as such, with the potential to be used in malaria elimination campaigns.
|
Antisporogonic activity against GFP expressing Plasmodium berghei ANKA infected in BALB/c mouse assessed as inhibition of appearance of oocysts in Anopheles gambiae level at 10 umol/kg, ip by microscopic analysis (Rvb = 83.6%)
|
Plasmodium berghei
|
35.5
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Novel endoperoxide-based transmission-blocking antimalarials with liver- and blood-schizontocidal activities.
Year : 2014
Volume : 5
Issue : 2
First Page : 108
Last Page : 112
Authors : Miranda D, Capela R, Albuquerque IS, Meireles P, Paiva I, Nogueira F, Amewu R, Gut J, Rosenthal PJ, Oliveira R, Mota MM, Moreira R, Marti F, Prudêncio M, O'Neill PM, Lopes F.
Abstract : In a search for effective compounds against both the blood- and liver-stages of infection by malaria parasites with the ability to block the transmission of the disease to mosquito vectors, a series of hybrid compounds combining either a 1,2,4-trioxane or 1,2,4,5-tetraoxane and 8-aminoquinoline moieties were synthesized and screened for their antimalarial activity. These hybrid compounds showed high potency against both exoerythrocytic and erythrocytic forms of malaria parasites, comparable to representative trioxane-based counterparts. Furthermore, they efficiently blocked the development of the sporogonic cycle in the mosquito vector. The tetraoxane-based hybrid 5, containing an amide linker between the two moieties, effectively cleared a patent blood-stage P. berghei infection in mice after i.p. administration. Overall, these results indicate that peroxide-8-aminoquinoline hybrids are excellent starting points to develop an agent that conveys all the desired antimalarial multistage activities in a single chemical entity and, as such, with the potential to be used in malaria elimination campaigns.
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum D6 by lactate dehydrogenase assay
|
Plasmodium falciparum D6
|
2.0
ug.mL-1
|
|
Journal : MedChemComm
Title : Extended side chain analogues of 8-aminoquinolines: Synthesis and evaluation of antiprotozoal, antimicrobial, -hematin inhibition, and cytotoxic activities
Year : 2011
Volume : 2
Issue : 4
First Page : 300
Last Page : 307
Authors : Kaur K, Jain M, Khan SI, Jacob MR, Tekwani BL, Singh S, Singh PP, Jain R
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum W2 by lactate dehydrogenase assay
|
Plasmodium falciparum
|
2.8
ug.mL-1
|
|
Journal : MedChemComm
Title : Extended side chain analogues of 8-aminoquinolines: Synthesis and evaluation of antiprotozoal, antimicrobial, -hematin inhibition, and cytotoxic activities
Year : 2011
Volume : 2
Issue : 4
First Page : 300
Last Page : 307
Authors : Kaur K, Jain M, Khan SI, Jacob MR, Tekwani BL, Singh S, Singh PP, Jain R
|
Cytotoxicity against African green monkey Vero cells by neutral red uptake assay
|
Chlorocebus sabaeus
|
23.8
ug.mL-1
|
|
Journal : MedChemComm
Title : Extended side chain analogues of 8-aminoquinolines: Synthesis and evaluation of antiprotozoal, antimicrobial, -hematin inhibition, and cytotoxic activities
Year : 2011
Volume : 2
Issue : 4
First Page : 300
Last Page : 307
Authors : Kaur K, Jain M, Khan SI, Jacob MR, Tekwani BL, Singh S, Singh PP, Jain R
|
Antileishmanial activity against Leishmania donovani promastigotes by Alamar Blue assay
|
Leishmania donovani
|
19.9
ug.mL-1
|
|
Journal : MedChemComm
Title : Extended side chain analogues of 8-aminoquinolines: Synthesis and evaluation of antiprotozoal, antimicrobial, -hematin inhibition, and cytotoxic activities
Year : 2011
Volume : 2
Issue : 4
First Page : 300
Last Page : 307
Authors : Kaur K, Jain M, Khan SI, Jacob MR, Tekwani BL, Singh S, Singh PP, Jain R
|
Antimalarial activity against liver stage of Plasmodium berghei infected in human Huh7 cells assessed as reduction in parasite load treated after 2 hrs of infection for 46 hrs by luciferase assay
|
Plasmodium berghei
|
3.4
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Octadecynoic acid as a dual life stage inhibitor of Plasmodium infections and plasmodial FAS-II enzymes.
Year : 2014
Volume : 24
Issue : 17
First Page : 4151
Last Page : 4157
Authors : Carballeira NM, Bwalya AG, Itoe MA, Andricopulo AD, Cordero-Maldonado ML, Kaiser M, Mota MM, Crawford AD, Guido RV, Tasdemir D.
Abstract : The malaria parasite Plasmodium goes through two life stages in the human host, a non-symptomatic liver stage (LS) followed by a blood stage with all clinical manifestation of the disease. In this study, we investigated a series of 2-alkynoic fatty acids (2-AFAs) with chain lengths between 14 and 18 carbon atoms for dual in vitro activity against both life stages. 2-Octadecynoic acid (2-ODA) was identified as the best inhibitor of Plasmodium berghei parasites with ten times higher potency (IC50=0.34 μg/ml) than the control drug. In target determination studies, the same compound inhibited three Plasmodium falciparum FAS-II (PfFAS-II) elongation enzymes PfFabI, PfFabZ, and PfFabG with the lowest IC50 values (0.28-0.80 μg/ml, respectively). Molecular modeling studies provided insights into the molecular aspects underlying the inhibitory activity of this series of 2-AFAs and a likely explanation for the considerably different inhibition potentials. Blood stages of P. falciparum followed a similar trend where 2-ODA emerged as the most active compound, with 20 times less potency. The general toxicity and hepatotoxicity of 2-AFAs were evaluated by in vitro and in vivo methods in mammalian cell lines and zebrafish models, respectively. This study identifies 2-ODA as the most promising antiparasitic 2-AFA, particularly towards P. berghei parasites.
|
Antimicrobial activity against chloroquine-sensitive Plasmodium falciparum 3D7
|
Plasmodium falciparum 3D7
|
460.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: a review.
Year : 2015
Volume : 90
First Page : 280
Last Page : 295
Authors : Mushtaque M, Shahjahan.
Abstract : Amongst several communicable diseases (CDs), malaria is one of the deadliest parasitic disease all over the world, particularly in African and Asian countries. To curb this menace, numbers of antimalarial agents are being sold as over the counter (OTC) drugs. Chloroquine (CQ) is one of them and is one of the oldest, cheapest, and easily available synthetic agents used to curb malaria. Unfortunately, after the reports of CQ-resistance against different strains of malarial parasite strains worldwide, scientist are continuously modifying the core structure of CQ to get an efficient drug. Interestingly, several new drugs have been emerged in due course having unique and enhanced properties (like dual stage inhibitors, resistance reversing ability etc.) and are ready to enter into the clinical trial. In this course, some new agents have also been discovered which are; though inactive against CQS strain, highly active against CQR strains. The present article describes the role of modification of the core structure of CQ and its effects on the biological activities. Moreover, the attempt has also been made to predict the future prospects of such drugs to reemerge as antimalarial agents.
|
Antimicrobial activity against Plasmodium falciparum Dd2
|
Plasmodium falciparum Dd2
|
460.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: a review.
Year : 2015
Volume : 90
First Page : 280
Last Page : 295
Authors : Mushtaque M, Shahjahan.
Abstract : Amongst several communicable diseases (CDs), malaria is one of the deadliest parasitic disease all over the world, particularly in African and Asian countries. To curb this menace, numbers of antimalarial agents are being sold as over the counter (OTC) drugs. Chloroquine (CQ) is one of them and is one of the oldest, cheapest, and easily available synthetic agents used to curb malaria. Unfortunately, after the reports of CQ-resistance against different strains of malarial parasite strains worldwide, scientist are continuously modifying the core structure of CQ to get an efficient drug. Interestingly, several new drugs have been emerged in due course having unique and enhanced properties (like dual stage inhibitors, resistance reversing ability etc.) and are ready to enter into the clinical trial. In this course, some new agents have also been discovered which are; though inactive against CQS strain, highly active against CQR strains. The present article describes the role of modification of the core structure of CQ and its effects on the biological activities. Moreover, the attempt has also been made to predict the future prospects of such drugs to reemerge as antimalarial agents.
|
Antimicrobial activity against chloroquine-resistant Plasmodium falciparum K1
|
Plasmodium falciparum K1
|
460.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: a review.
Year : 2015
Volume : 90
First Page : 280
Last Page : 295
Authors : Mushtaque M, Shahjahan.
Abstract : Amongst several communicable diseases (CDs), malaria is one of the deadliest parasitic disease all over the world, particularly in African and Asian countries. To curb this menace, numbers of antimalarial agents are being sold as over the counter (OTC) drugs. Chloroquine (CQ) is one of them and is one of the oldest, cheapest, and easily available synthetic agents used to curb malaria. Unfortunately, after the reports of CQ-resistance against different strains of malarial parasite strains worldwide, scientist are continuously modifying the core structure of CQ to get an efficient drug. Interestingly, several new drugs have been emerged in due course having unique and enhanced properties (like dual stage inhibitors, resistance reversing ability etc.) and are ready to enter into the clinical trial. In this course, some new agents have also been discovered which are; though inactive against CQS strain, highly active against CQR strains. The present article describes the role of modification of the core structure of CQ and its effects on the biological activities. Moreover, the attempt has also been made to predict the future prospects of such drugs to reemerge as antimalarial agents.
|
Antiplasmodial activity against blood stage of chloroquine-sensitive Plasmodium falciparum NF54 by parasite lactate dehydrogenase assay
|
Plasmodium falciparum NF54
|
892.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Primaquine-pyrimidine hybrids: synthesis and dual-stage antiplasmodial activity.
Year : 2015
Volume : 101
First Page : 266
Last Page : 273
Authors : Kaur H, Machado M, de Kock C, Smith P, Chibale K, Prudêncio M, Singh K.
Abstract : A series of novel pyrimidine-primaquine hybrids were synthesized and their effectiveness against the blood and liver stages of malaria parasites was evaluated. The hybrids displayed enhanced liver stage in vitro activity against P. berghei liver stage infection.
|
Inhibition of beta-haematin formation after 18 hrs by spectrophotometric analysis relative to haematin
|
None
|
10.0
equiv
|
|
Journal : MedChemComm
Title : Discovery of oxybisbenzoylamides as a new class of antimalarial agents
Year : 2015
Volume : 6
Issue : 6
First Page : 1173
Last Page : 1177
Authors : Pancotti A, Parapini S, Dell'Agli M, Gambini L, Galli C, Sangiovanni E, Basilico N, Bosisio E, Taramelli D, Romeo S
|
Antimalarial activity against sporozoite stage of Plasmodium berghei infected in human Huh7 cells assessed as inhibition of parasite infection at 10 uM pre-incubated for 24 hrs followed by parasite infection measured after 48 hrs by bioluminescence assay
|
Plasmodium berghei
|
62.0
%
|
|
Journal : J. Med. Chem.
Title : Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials?
Year : 2016
Volume : 59
Issue : 1
First Page : 264
Last Page : 281
Authors : Terzić N, Konstantinović J, Tot M, Burojević J, Djurković-Djaković O, Srbljanović J, Štajner T, Verbić T, Zlatović M, Machado M, Albuquerque IS, Prudêncio M, Sciotti RJ, Pecic S, D'Alessandro S, Taramelli D, Šolaja BA.
Abstract : The syntheses and antiplasmodial activities of various substituted aminoquinolines coupled to an adamantane carrier are described. The compounds exhibited pronounced in vitro and in vivo activity against Plasmodium berghei in the Thompson test. Tethering a fluorine atom to the aminoquinoline C(3) position afforded fluoroaminoquinolines that act as intrahepatocytic parasite inhibitors, with compound 25 having an IC50 = 0.31 μM and reducing the liver load in mice by up to 92% at 80 mg/kg dose. Screening our peroxides as inhibitors of liver stage infection revealed that the tetraoxane pharmacophore itself is also an excellent liver stage P. berghei inhibitor (78: IC50 = 0.33 μM). Up to 91% reduction of the parasite liver load in mice was achieved at 100 mg/kg. Examination of tetraoxane 78 against the transgenic 3D7 strain expressing luciferase under a gametocyte-specific promoter revealed its activity against stage IV-V Plasmodium falciparum gametocytes (IC50 = 1.16 ± 0.37 μM). To the best of our knowledge, compounds 25 and 78 are the first examples of either an 4-aminoquinoline or a tetraoxane liver stage inhibitors.
|
Antimalarial activity against liver stage form of luciferase transfected Plasmodium berghei sporozoites infected in mouse assessed as inhibition of parasitemia at 50 mg/kg administered via oral gavage 1 hr post infection measured on day 9 by bioluminescence method relative to control
|
Plasmodium berghei
|
99.0
%
|
|
Journal : J Med Chem
Title : Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure-Activity and Structure-Property Relationship Studies.
Year : 2018
Volume : 61
Issue : 4
First Page : 1450
Last Page : 1473
Authors : Neelarapu R, Maignan JR, Lichorowic CL, Monastyrskyi A, Mutka TS, LaCrue AN, Blake LD, Casandra D, Mashkouri S, Burrows JN, Willis PA, Kyle DE, Manetsch R.
Abstract : Malaria deaths have been decreasing over the last 10-15 years, with global mortality rates having fallen by 47% since 2000. While the World Health Organization (WHO) recommends the use of artemisinin-based combination therapies (ACTs) to combat malaria, the emergence of artemisinin resistant strains underscores the need to develop new antimalarial drugs. Recent in vivo efficacy improvements of the historical antimalarial ICI 56,780 have been reported, however, with the poor solubility and rapid development of resistance, this compound requires further optimization. A series of piperazine-containing 4(1H)-quinolones with greatly enhanced solubility were developed utilizing structure-activity relationship (SAR) and structure-property relationship (SPR) studies. Furthermore, promising compounds were chosen for an in vivo scouting assay to narrow selection for testing in an in vivo Thompson test. Finally, two piperazine-containing 4(1H)-quinolones were curative in the conventional Thompson test and also displayed in vivo activity against the liver stages of the parasite.
|
Antiplasmodial activity against Plasmodium falciparum FCR-3 sporozoites infected in human primary hepatocytes treated simultaneously with infection by DAPI staining based HCS analysis
|
Plasmodium falciparum FCR-3/Gambia
|
400.0
nM
|
|
Journal : Eur J Med Chem
Title : Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery.
Year : 2018
Volume : 152
First Page : 489
Last Page : 514
Authors : Quiliano M, Pabón A, Moles E, Bonilla-Ramirez L, Fabing I, Fong KY, Nieto-Aco DA, Wright DW, Pizarro JC, Vettorazzi A, López de Cerain A, Deharo E, Fernández-Busquets X, Garavito G, Aldana I, Galiano S.
Abstract : Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro (55, 56, 61, 64, 66, and 70-73) and in vivo (66 and 72) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei. Compounds 55, 56, 61, 64, 66 and 70-73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC50s < 0.28 μM), and compounds 55, 56, 64, 70, 71, and 72 showed potent biological activity in chloroquine-sensitive and multidrug-resistant strains (IC50s < 0.7 μM for 3D7, D6, FCR-3 and C235). All of these compounds share appropriate drug-likeness profiles and adequate selectivity indexes (77 < SI < 184) as well as lack genotoxicity. In vivo efficacy tests in a mouse model showed compounds 66 and 72 to be promising candidates as they exhibited significant parasitemia reductions of 96.4% and 80.4%, respectively. Additional studies such as liver stage and sporogony inhibition, target exploration of heat shock protein 90 of P. falciparum, targeted delivery by immunoliposomes, and enantiomer characterization were performed and strongly reinforce the hypothesis of 1-aryl-3-substituted propanol derivatives as promising antimalarial compounds.
|
Antiplasmodial activity against GFP-harboring Plasmodium falciparum sporozoites infected in human primary hepatocytes assessed as reduction in parasite growth treated every 24 hrs by DAPI staining-based fluorescence microscopic analysis
|
Plasmodium falciparum
|
400.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel antimalarial chloroquine- and primaquine-quinoxaline 1,4-di-N-oxide hybrids: Design, synthesis, Plasmodium life cycle stage profile, and preliminary toxicity studies.
Year : 2018
Volume : 158
First Page : 68
Last Page : 81
Authors : Bonilla-Ramirez L, Rios A, Quiliano M, Ramirez-Calderon G, Beltrán-Hortelano I, Franetich JF, Corcuera L, Bordessoulles M, Vettorazzi A, López de Cerain A, Aldana I, Mazier D, Pabón A, Galiano S.
Abstract : Emergence of drug resistance and targeting all stages of the parasite life cycle are currently the major challenges in antimalarial chemotherapy. Molecular hybridization combining two scaffolds in a single molecule is an innovative strategy for achieving these goals. In this work, a series of novel quinoxaline 1,4-di-N-oxide hybrids containing either chloroquine or primaquine pharmacophores was designed, synthesized and tested against both chloroquine sensitive and multidrug resistant strains of Plasmodium falciparum. Only chloroquine-based compounds exhibited potent blood stage activity with compounds 4b and 4e being the most active and selective hybrids at this parasite stage. Based on their intraerythrocytic activity and selectivity or their chemical nature, seven hybrids were then evaluated against the liver stage of Plasmodium yoelii, Plasmodium berghei and Plasmodium falciparum infections. Compound 4b was the only chloroquine-quinoxaline 1,4-di-N-oxide hybrid with a moderate liver activity, whereas compound 6a and 6b were identified as the most active primaquine-based hybrids against exoerythrocytic stages, displaying enhanced liver activity against P. yoelii and P. berghei, respectively, and better SI values than primaquine. Although both primaquine-quinoxaline 1,4-di-N-oxide hybrids slightly reduced the infection of mosquitoes, they inhibited sporogony of P. berghei and compound 6a showed 92% blocking of transmission. In vivo liver efficacy assays revealed that compound 6a showed causal prophylactic activity affording parasitaemia reduction of up to 95% on day 4. Absence of genotoxicity and in vivo acute toxicity were also determined. These results suggest the approach of primaquine-quinoxaline 1,4-di-N-oxide hybrids as new potential dual-acting antimalarials for further investigation.
|
Antimalarial activity against Plasmodium falciparum liver stage form infected in human primary hepatocytes assessed as reduction in viability at 19.3 uM incubated for 3 days followed by compound wash and measured on day 6 relative to control
|
Plasmodium falciparum
|
90.0
%
|
|
Journal : J Nat Prod
Title : Friomaramide, a Highly Modified Linear Hexapeptide from an Antarctic Sponge, Inhibits <i>Plasmodium falciparum</i> Liver-Stage Development.
Year : 2019
Volume : 82
Issue : 8
First Page : 2354
Last Page : 2358
Authors : Knestrick MA, Wilson NG, Roth A, Adams JH, Baker BJ.
Abstract : The cold waters of Antarctica are known to harbor a rich biodiversity. Our continuing interest in the chemical analysis of Antarctic invertebrates has resulted in the isolation of friomaramide (<b>1</b>), a new, highly modified hexapeptide, from the Antarctic sponge <i>Inflatella coelosphaeroides</i>. The structure of friomaramide was determined using spectroscopic methods and its configuration established by Marfey's method. Friomaramide, which bears the unusual permethylation of the amino acid backbone and is the longest polypeptide bearing a tryptenamine C-terminus, blocks >90% of <i>Plasmodium falciparum</i> liver-stage parasite development at 6.1 μM.
|
Inhibition of Escherichia coli GroEL expressed in Escherichia coliDH5alpha/Escherichia coli GroES expressed in Escherichia coli BL21 (DE3) assessed as reduction in GroEL/GroES-mediated denatured soluble pig heart MDH refolding by measuring MDH enzyme activity using sodium mesoxalate as substrate after 20 to 40 mins by malachite green dye based spectrometric analysis relative to untreated control
|
Escherichia coli
|
81.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules.
Year : 2019
Volume : 29
Issue : 9
First Page : 1106
Last Page : 1112
Authors : Stevens M, Abdeen S, Salim N, Ray AM, Washburn A, Chitre S, Sivinski J, Park Y, Hoang QQ, Chapman E, Johnson SM.
Abstract : All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 - also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma brucei parasites) and drug-resistant bacterial infections (in particular Methicillin-resistant Staphylococcus aureus - MRSA). Intriguingly, during our studies we found that three known antibiotics - suramin, closantel, and rafoxanide - were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3680 approved drugs, natural products, and known bioactives identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition.
|
Inhibition of Escherichia coli GroEL expressed in Escherichia coli DH5alpha/Escherichia coli GroES expressed in Escherichia coli BL21 (DE3) assessed as reduction in GroEL/GroES-mediated denatured rhodanese refolding by measuring rhodanese enzyme activity after 45 mins by Fe(SCN)3 dye based spectrometric analysis relative to untreated control
|
Escherichia coli
|
94.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules.
Year : 2019
Volume : 29
Issue : 9
First Page : 1106
Last Page : 1112
Authors : Stevens M, Abdeen S, Salim N, Ray AM, Washburn A, Chitre S, Sivinski J, Park Y, Hoang QQ, Chapman E, Johnson SM.
Abstract : All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 - also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma brucei parasites) and drug-resistant bacterial infections (in particular Methicillin-resistant Staphylococcus aureus - MRSA). Intriguingly, during our studies we found that three known antibiotics - suramin, closantel, and rafoxanide - were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3680 approved drugs, natural products, and known bioactives identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition.
|
Inhibition of His-tagged human recombinant SHMT2 expressed in Escherichia coli BLR(DE3) assessed as reduction in NADPH level using L-serine, THF and NADP+ at 6.5 or 26.5 uM incubated for 5 mins by SHMT2-MTHFD coupled reaction based fluorescence assay relative to control
|
Homo sapiens
|
91.9
%
|
|
Title : Compositions and methods relating to inhibiting serine hyrdoxymethyltransferase 2 activity
|
Inhibition of His-tagged human recombinant SHMT2 expressed in Escherichia coli BLR(DE3) assessed as reduction in NADPH level using L-serine, THF and NADP+ incubated for 5 mins by SHMT2-MTHFD coupled reaction based fluorescence assay
|
Homo sapiens
|
436.52
nM
|
|
Title : Compositions and methods relating to inhibiting serine hyrdoxymethyltransferase 2 activity
|
Growth inhibiting activity of Naegleria gruberi in vitro
|
Naegleria gruberi
|
10.7
%
|
|
Title : Naegleria gruberi Pathogen Box compounds screening
Authors : Sarink, M; Mykytyn, A; Tielens, A; van Hellemond, J
Abstract : 400 compounds from the Pathogen box were screened for inhibitory activity against Naegleria gruberi strain NEG-M. N. gruberi was grown in modified PYNFH medium in 96-wells plates. Compounds were added in 10 uM concentrations in triplicate wells. Optical density was measured daily, after 6 days area under the curve was calculated and compared to 0.1 % DMSO control.
|
Antimalarial activity against Plasmodium gallinaceum vectored in Aedes fluviatilis infected in chicken assessed as reduction in mosquito infection at 15 mg/kg, po measured after 4 hrs by Giemsa staining based microscopic analysis relative to control
|
Plasmodium gallinaceum
|
100.0
%
|
|
Journal : Bioorg Med Chem
Title : Antimalarial and anti-inflammatory activities of new chloroquine and primaquine hybrids: Targeting the blockade of malaria parasite transmission.
Year : 2020
Volume : 28
Issue : 24
First Page : 115832
Last Page : 115832
Authors : Boechat N,Carvalho RCC,Ferreira MLG,Coutinho JP,Sa PM,Seito LN,Rosas EC,Krettli AU,Bastos MM,Pinheiro LCS
Abstract : Malaria is a disease that requires new drugs not only to fight Plasmodium but also to reduce symptoms of infection such as fever and inflammation. A series of 21 hybrid compounds were designed from chloroquine (CQ) and primaquine (PQ) linked to the pharmacophoric group present in phenylacetic anti-inflammatory drugs. These compounds were designed to have dual activity: namely, to be capable of killing Plasmodium and still act on the inflammatory process caused by malaria infection. The compounds were assayed with nine different biological methods. The carbonylated CQ derivative 6 (n = 3; R = Cl) was more potent than CQ in vitro, and 8 (n = 4; R = H) reduced P. berghei parasitemia up to 37% on day 7. The carbonylated PQ derivative 17 (R = Br) was slightly less potent than PQ. The gem-difluoro PQ derivative 20 (R = Cl) exhibited high transmission blockade of the malaria sporogonic cycle in mosquitoes. Compounds 6 and 20 dose-dependently reduced nitric oxide (NO) production and inhibited TNFα production by LPS-stimulated J774A.1 macrophages. Our results indicate a viable and interesting approach in planning new chemical entities that act as transmission-blocking drugs for treating malaria caused by P. falciparum and P. vivax and the anti-inflammatory process related to this disease.
|
Antimalarial activity against liver stage Plasmodium berghei PbmCherryhsp70 sporozoites infected in human HepG2 cells assessed as reduction in parasite number at 8 uM incubated for 24 hrs followed by removal of media and supplemented with fresh media and further incubated for 24 hrs by phase contrast microscopic analysis relative to control
|
Plasmodium berghei
|
50.0
%
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of benzhydryl-based antiplasmodial agents possessing Plasmodium falciparum chloroquine resistance transporter (PfCRT) inhibitory activity.
Year : 2021
Volume : 215
First Page : 113227
Last Page : 113227
Authors : Relitti N,Federico S,Pozzetti L,Butini S,Lamponi S,Taramelli D,D'Alessandro S,Martin RE,Shafik SH,Summers RL,Babij SK,Habluetzel A,Tapanelli S,Caldelari R,Gemma S,Campiani G
Abstract : Due to the surge in resistance to common therapies, malaria remains a significant concern to human health worldwide. In chloroquine (CQ)-resistant (CQ-R) strains of Plasmodium falciparum, CQ and related drugs are effluxed from the parasite's digestive vacuole (DV). This process is mediated by mutant isoforms of a protein called CQ resistance transporter (PfCRT). CQ-R strains can be partially re-sensitized to CQ by verapamil (VP), primaquine (PQ) and other compounds, and this has been shown to be due to the ability of these molecules to inhibit drug transport via PfCRT. We have previously developed a series of clotrimazole (CLT)-based antimalarial agents that possess inhibitory activity against PfCRT (4a,b). In our endeavor to develop novel PfCRT inhibitors, and to perform a structure-activity relationship analysis, we synthesized a new library of analogues. When the benzhydryl system was linked to a 4-aminoquinoline group (5a-f) the resulting compounds exhibited good cytotoxicity against both CQ-R and CQ-S strains of P. falciparum. The most potent inhibitory activity against the PfCRT-mediated transport of CQ was obtained with compound 5k. When compared to the reference compound, benzhydryl analogues of PQ (5i,j) showed a similar activity against blood-stage parasites, and a stronger in vitro potency against liver-stage parasites. Unfortunately, in the in vivo transmission blocking assays, 5i,j were inactive against gametocytes.
