|
Evaluated for the neurotoxicity against NB2a Neuroblastoma cells.
|
Mus musculus
|
351.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antimalarial activity of sixteen dispiro-1,2,4, 5-tetraoxanes: alkyl-substituted 7,8,15,16-tetraoxadispiro[5.2.5. 2]hexadecanes.
Year : 2000
Volume : 43
Issue : 14
First Page : 2753
Last Page : 2758
Authors : Vennerstrom JL, Dong Y, Andersen SL, Ager AL, Fu H, Miller RE, Wesche DL, Kyle DE, Gerena L, Walters SM, Wood JK, Edwards G, Holme AD, McLean WG, Milhous WK.
Abstract : Sixteen alkyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15, 16-tetraoxadispiro[5.2.5.2]hexadecanes) were synthesized to explore dispiro-1,2,4,5-tetraoxane SAR and to identify tetraoxanes with better oral antimalarial activity than prototype tetraoxane 1 (WR 148999). The tetraoxanes were prepared either by peroxidation of the corresponding cyclohexanone derivatives in H(2)SO(4)/CH(3)CN or by ozonolysis of the corresponding cyclohexanone methyl oximes. Those tetraoxanes with alkyl substituents at the 1 and 10 positions were formed as single stereoisomers, whereas the five tetraoxanes formed without the stereochemical control provided by alkyl groups at the 1 and 10 positions were isolated as mixtures of diastereomers. Three of the sixteen tetraoxanes were inactive (IC(50)'s > 1000 nM), but five (2, 6, 10, 11, 12) had IC(50)'s between 10 and 30 nM against the chloroquine-sensitive D6 and chloroquine-resistant W2 clones of Plasmodium falciparum compared to corresponding IC(50)'s of 55 and 32 nM for 1 and 8.4 and 7.3 nM for artemisinin. We suggest that tetraoxanes 13, 16, and 17 were inactive and tetraoxanes 4 and 7 were weakly active due to steric effects preventing or hindering peroxide bond access to parasite heme. Tetraoxanes 1, 10, 11, and 14, along with artemisinin and arteether as controls, were administered po b.i.d. (128 mg/kg/day) to P. berghei-infected mice on days 3, 4, and 5 post-infection. At this dose, tetraoxanes 10, 11, and 14 cured between 40% and 60% of the infected animals. In comparison, artemisinin and tetraoxane 1 produced no cures, whereas arteether cured 100% of the infected animals. There was no apparent relationship between tetraoxane structure and in vitro neurotoxicity, nor was there any correlation between antimalarial activity and neurotoxicity for these seventeen tetraoxanes.
|
In vitro anti-protozoal activity against Plasmodium falciparum Ghana
|
Plasmodium falciparum
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1,4-Dihydroxy-2,3-dioxatricyclo[8.4.0.0(4,9)]tetradecane and derivatives with in vitro activity against Plasmodium falciparum, Trypanasoma b brucei, Trypanasoma cruzi, and Leishmaniasis infantum.
Year : 2003
Volume : 13
Issue : 12
First Page : 2013
Last Page : 2015
Authors : Howarth J, Wilson D.
Abstract : 1,4-Dihydroxy-2,3-dioxatricyclo[8.4.0.0(4,9)]tetradecane and derivatives have been synthesised and their in vitro activity against Plasmodium falciparum (malaria) Ghana, Trypanasoma b brucei (sleeping sickness) TB-1, and Trypanasoma cruzi (Chagas' disease) TC-1, and Leishmaniasis infantum (leishmaniasis) L1 parasite strains has been assessed.
|
In vitro antimalarial activity against Plasmodium falciparum FCR3
|
Plasmodium falciparum
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antimalarial activity of 2-methoxyprop-2-yl peroxides derivatives.
Year : 2003
Volume : 13
Issue : 1
First Page : 75
Last Page : 77
Authors : Cointeaux L, Berrien JF, Peyrou V, Provot O, Ciceron L, Danis M, Robert A, Meunier B, Mayrargue J.
Abstract : 2-Methoxyprop-2-yl peroxides were synthesized and evaluated in vitro against Plasmodium falciparum. These acyclic artemisinin-related peroxides revealed moderate to good activity but were devoid of alkylating property towards the synthetic model of heme Mn(II)-TPP.
|
In vitro antimalarial activity against chloroquine-sensitive Plasmodium falciparum HB3
|
Plasmodium falciparum
|
3.42
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, antimalarial activity, biomimetic iron(II) chemistry, and in vivo metabolism of novel, potent C-10-phenoxy derivatives of dihydroartemisinin.
Year : 2001
Volume : 44
Issue : 1
First Page : 58
Last Page : 68
Authors : O'Neill PM, Miller A, Bishop LP, Hindley S, Maggs JL, Ward SA, Roberts SM, Scheinmann F, Stachulski AV, Posner GH, Park BK.
Abstract : The combination of TMSOTf and AgClO(4) promotes the efficient C-10-phenoxylation of dihydroartemisinin (3) in good chemical yield and excellent stereoselectivity. All of the new phenoxy derivatives have potent in vitro antimalarial activity. On the basis of the excellent yield and stereoselectivity obtained for the p-trifluoromethyl derivative 7b, this compound and the parent phenyl-substituted derivative 5b were selected for in vivo biological evaluation against Plasmodium berghei in the mouse model and for metabolism studies in rats. Compound 7b demonstrated excellent in vivo antimalarial potency with an ED(50) of 2.12 mg/kg (cf. artemether = 6 mg/kg) versus P. berghei. Furthermore, from preliminary metabolism studies, this compound was not metabolized to dihydroartemisinin; suggesting it should have a longer half-life and potentially lower toxicity than the first-generation derivatives artemether and arteether. From biomimetic Fe(II)-catalyzed decomposition studies and ESR spectroscopy, the mechanism of action of these new lead antimalarials is proposed to involve the formation of both primary and secondary C-centered cytotoxic radicals which presumably react with vital parasite thiol-containing cellular macromolecules.
|
In vitro antimalarial activity against chloroquine-resistant Plasmodium falciparum K1
|
Plasmodium falciparum
|
4.55
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, antimalarial activity, biomimetic iron(II) chemistry, and in vivo metabolism of novel, potent C-10-phenoxy derivatives of dihydroartemisinin.
Year : 2001
Volume : 44
Issue : 1
First Page : 58
Last Page : 68
Authors : O'Neill PM, Miller A, Bishop LP, Hindley S, Maggs JL, Ward SA, Roberts SM, Scheinmann F, Stachulski AV, Posner GH, Park BK.
Abstract : The combination of TMSOTf and AgClO(4) promotes the efficient C-10-phenoxylation of dihydroartemisinin (3) in good chemical yield and excellent stereoselectivity. All of the new phenoxy derivatives have potent in vitro antimalarial activity. On the basis of the excellent yield and stereoselectivity obtained for the p-trifluoromethyl derivative 7b, this compound and the parent phenyl-substituted derivative 5b were selected for in vivo biological evaluation against Plasmodium berghei in the mouse model and for metabolism studies in rats. Compound 7b demonstrated excellent in vivo antimalarial potency with an ED(50) of 2.12 mg/kg (cf. artemether = 6 mg/kg) versus P. berghei. Furthermore, from preliminary metabolism studies, this compound was not metabolized to dihydroartemisinin; suggesting it should have a longer half-life and potentially lower toxicity than the first-generation derivatives artemether and arteether. From biomimetic Fe(II)-catalyzed decomposition studies and ESR spectroscopy, the mechanism of action of these new lead antimalarials is proposed to involve the formation of both primary and secondary C-centered cytotoxic radicals which presumably react with vital parasite thiol-containing cellular macromolecules.
|
In vitro antimalarial activity for Plasmodium falciparum W-2
|
Plasmodium falciparum
|
5.4
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antimalarial activities of fluoroalkyl derivatives of dihydroartemisinin.
Year : 1998
Volume : 41
Issue : 21
First Page : 4101
Last Page : 4108
Authors : Thanh Nga TT, Ménage C, Bégué JP, Bonnet-Delpon D, Gantier JC, Pradines B, Doury JC, Thac TD.
Abstract : Fluoroalkyl ethers (4) of dihydroartemisinin (2) have been prepared by reaction of fluoroalkyl alcohols with dihydroartemisinin by different methods (BF3,Et2O or TMSCl catalysis or Mitsunobu reaction). Ethers 4a-d derived from primary fluoroalkyl alcohols were obtained in moderate to good yields by these methods. Ethers 4e-j have been prepared from fluoroalkyl secondary and tertiary alcohols and phenol using the Mitsunobu reaction. Although in vitro antimalarial activities of ethers toward Plasmodium falciparum W-2 asiatic strain are moderate, in vivo activities against Plasmodium berghei (NT 173) are excellent.
|
In vitro inhibitory activity against the chloroquine-resistant Plasmodium falciparum W2 Indochina
|
Plasmodium falciparum
|
5.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Alkylation of manganese(II) tetraphenylporphyrin by antimalarial fluorinated artemisinin derivatives.
Year : 2003
Volume : 13
Issue : 6
First Page : 1059
Last Page : 1062
Authors : Rodriguez M, Bonnet-Delpon D, Bégué JP, Robert A, Meunier B.
Abstract : The alkylating properties of two artemisinin derivatives bearing a trifluoromethyl substituent at C10 were evaluated toward manganese(II) tetraphenylporphyrin, considered as a heme model. Chlorin-type covalent adducts were obtained by alkylation of the porphyrin ring by C-centered radicals derived from reductive activation of the peroxide function of the drugs.
|
In vitro inhibitory concentration against chloroquine-sensitive Plasmodium falciparum HB3
|
Plasmodium falciparum
|
9.2
nM
|
|
Journal : J. Med. Chem.
Title : Mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of new diamine containing analogues.
Year : 2002
Volume : 45
Issue : 5
First Page : 1052
Last Page : 1063
Authors : Hindley S, Ward SA, Storr RC, Searle NL, Bray PG, Park BK, Davies J, O'Neill PM.
Abstract : The potent antimalarial activity of chloroquine against chloroquine-sensitive strains can be attributed, in part, to its high accumulation in the acidic environment of the heme-rich parasite food vacuole. A key component of this intraparasitic chloroquine accumulation mechanism is a weak base "ion-trapping" effect whereupon the basic drug is concentrated in the acidic food vacuole in its membrane-impermeable diprotonated form. By the incorporation of amino functionality into target artemisinin analogues, we hoped to prepare a new series of analogues that, by virtue of increased accumulation into the ferrous-rich vacuole, would display enhanced antimalarial potency. The initial part of the project focused on the preparation of piperazine-linked analogues (series 1 (7-16)). Antimalarial evaluation of these derivatives demonstrated potent activity versus both chloroquine-sensitive and chloroquine-resistant parasites. On the basis of these observations, we then set about preparing a series of C-10 carba-linked amino derivatives. Optimization of the key synthetic step using a newly developed coupling protocol provided a key intermediate, allyldeoxoartemisinin (17) in 90% yield. Further elaboration, in three steps, provided nine target C-10 carba analogues (series 2 (21-29)) in good overall yields. Antimalarial assessment demonstrated that these compounds were 4-fold more potent than artemisinin and about twice as active as artemether in vitro versus chloroquine-resistant parasites. On the basis of the products obtained from biomimetic Fe(II) degradation of the C-10 carba analogue (23), we propose that these analogues may have a mode of action subtly different from that of the parent drug artemisinin (series 1 (7-16)) and other C-10 ether derivatives such as artemether. Preliminary in vivo testing by the WHO demonstrated that four of these compounds are active orally at doses of less than 10 mg/kg. Since these analogues are available as water-soluble salts and cannot form dihydroartemisinin by P450-catalyzed oxidation, they represent useful leads that might prove to be superior to the currently used derivatives, artemether and artesunate.
|
In vitro inhibitory concentration against chloroquine-resistant Plasmodium falciparum K1
|
Plasmodium falciparum
|
6.5
nM
|
|
Journal : J. Med. Chem.
Title : Mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of new diamine containing analogues.
Year : 2002
Volume : 45
Issue : 5
First Page : 1052
Last Page : 1063
Authors : Hindley S, Ward SA, Storr RC, Searle NL, Bray PG, Park BK, Davies J, O'Neill PM.
Abstract : The potent antimalarial activity of chloroquine against chloroquine-sensitive strains can be attributed, in part, to its high accumulation in the acidic environment of the heme-rich parasite food vacuole. A key component of this intraparasitic chloroquine accumulation mechanism is a weak base "ion-trapping" effect whereupon the basic drug is concentrated in the acidic food vacuole in its membrane-impermeable diprotonated form. By the incorporation of amino functionality into target artemisinin analogues, we hoped to prepare a new series of analogues that, by virtue of increased accumulation into the ferrous-rich vacuole, would display enhanced antimalarial potency. The initial part of the project focused on the preparation of piperazine-linked analogues (series 1 (7-16)). Antimalarial evaluation of these derivatives demonstrated potent activity versus both chloroquine-sensitive and chloroquine-resistant parasites. On the basis of these observations, we then set about preparing a series of C-10 carba-linked amino derivatives. Optimization of the key synthetic step using a newly developed coupling protocol provided a key intermediate, allyldeoxoartemisinin (17) in 90% yield. Further elaboration, in three steps, provided nine target C-10 carba analogues (series 2 (21-29)) in good overall yields. Antimalarial assessment demonstrated that these compounds were 4-fold more potent than artemisinin and about twice as active as artemether in vitro versus chloroquine-resistant parasites. On the basis of the products obtained from biomimetic Fe(II) degradation of the C-10 carba analogue (23), we propose that these analogues may have a mode of action subtly different from that of the parent drug artemisinin (series 1 (7-16)) and other C-10 ether derivatives such as artemether. Preliminary in vivo testing by the WHO demonstrated that four of these compounds are active orally at doses of less than 10 mg/kg. Since these analogues are available as water-soluble salts and cannot form dihydroartemisinin by P450-catalyzed oxidation, they represent useful leads that might prove to be superior to the currently used derivatives, artemether and artesunate.
|
In vitro inhibitory concentration against chloroquine-resistant Plasmodium falciparum K1
|
Plasmodium falciparum
|
7.94
nM
|
|
Journal : J. Med. Chem.
Title : Mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of new diamine containing analogues.
Year : 2002
Volume : 45
Issue : 5
First Page : 1052
Last Page : 1063
Authors : Hindley S, Ward SA, Storr RC, Searle NL, Bray PG, Park BK, Davies J, O'Neill PM.
Abstract : The potent antimalarial activity of chloroquine against chloroquine-sensitive strains can be attributed, in part, to its high accumulation in the acidic environment of the heme-rich parasite food vacuole. A key component of this intraparasitic chloroquine accumulation mechanism is a weak base "ion-trapping" effect whereupon the basic drug is concentrated in the acidic food vacuole in its membrane-impermeable diprotonated form. By the incorporation of amino functionality into target artemisinin analogues, we hoped to prepare a new series of analogues that, by virtue of increased accumulation into the ferrous-rich vacuole, would display enhanced antimalarial potency. The initial part of the project focused on the preparation of piperazine-linked analogues (series 1 (7-16)). Antimalarial evaluation of these derivatives demonstrated potent activity versus both chloroquine-sensitive and chloroquine-resistant parasites. On the basis of these observations, we then set about preparing a series of C-10 carba-linked amino derivatives. Optimization of the key synthetic step using a newly developed coupling protocol provided a key intermediate, allyldeoxoartemisinin (17) in 90% yield. Further elaboration, in three steps, provided nine target C-10 carba analogues (series 2 (21-29)) in good overall yields. Antimalarial assessment demonstrated that these compounds were 4-fold more potent than artemisinin and about twice as active as artemether in vitro versus chloroquine-resistant parasites. On the basis of the products obtained from biomimetic Fe(II) degradation of the C-10 carba analogue (23), we propose that these analogues may have a mode of action subtly different from that of the parent drug artemisinin (series 1 (7-16)) and other C-10 ether derivatives such as artemether. Preliminary in vivo testing by the WHO demonstrated that four of these compounds are active orally at doses of less than 10 mg/kg. Since these analogues are available as water-soluble salts and cannot form dihydroartemisinin by P450-catalyzed oxidation, they represent useful leads that might prove to be superior to the currently used derivatives, artemether and artesunate.
|
In vitro inhibitory concentration against chloroquine-resistant Plasmodium falciparum FcB1
|
Plasmodium falciparum
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : Orally active antimalarials: hydrolytically stable derivatives of 10-trifluoromethyl anhydrodihydroartemisinin.
Year : 2004
Volume : 47
Issue : 6
First Page : 1423
Last Page : 1433
Authors : Grellepois F, Chorki F, Ourévitch M, Charneau S, Grellier P, McIntosh KA, Charman WN, Pradines B, Crousse B, Bonnet-Delpon D, Bégué JP.
Abstract : New fluoroartemisinin derivatives containing polar or water-soluble functionalities at C-16 (11a-j, 12a-g) were synthesized using the key intermediate 16-bromo-10-trifluoromethyl anhydrodihydroartemisinin 10. The substitution reaction from 10 was more selective than that from the nonfluorinated parent bromide; the allylic bromide 10 underwent no allylic rearrangement and provided only nucleophilic substitution products in high yields with N-, O-, and C-nucleophiles. Among them, amines 11a-c appeared to be highly in vivo efficient antimalarials on mice infected with Plasmodium berghei, more than the reference sodium artesunate 1d. In particular, the most effective piperazinoethanol derivative 11b cured all mice after oral treatment at a dose lower than 10 mg/kg. Further pharmacokinetic studies showed that the bioavailability in rats following oral administration was 25 times greater for 11b than for artemether 1b.
|
Inhibitory concentration against Plasmodium falciparum D6 (Sierra Leone)
|
Plasmodium falciparum
|
4.49
nM
|
|
Journal : J. Med. Chem.
Title : Arteether, a new antimalarial drug: synthesis and antimalarial properties.
Year : 1988
Volume : 31
Issue : 3
First Page : 645
Last Page : 650
Authors : Brossi A, Venugopalan B, Dominguez Gerpe L, Yeh HJ, Flippen-Anderson JL, Buchs P, Luo XD, Milhous W, Peters W.
Abstract : Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.
|
Inhibitory concentration against Plasmodium falciparum W2 Indochina
|
Plasmodium falciparum
|
3.34
nM
|
|
Journal : J. Med. Chem.
Title : Arteether, a new antimalarial drug: synthesis and antimalarial properties.
Year : 1988
Volume : 31
Issue : 3
First Page : 645
Last Page : 650
Authors : Brossi A, Venugopalan B, Dominguez Gerpe L, Yeh HJ, Flippen-Anderson JL, Buchs P, Luo XD, Milhous W, Peters W.
Abstract : Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.
|
Intrinsic equimolar activity against Plasmodium falciparum D6 (Sierra Leone) relative to QHS
|
Plasmodium falciparum
|
2.34
nM
|
|
Journal : J. Med. Chem.
Title : Arteether, a new antimalarial drug: synthesis and antimalarial properties.
Year : 1988
Volume : 31
Issue : 3
First Page : 645
Last Page : 650
Authors : Brossi A, Venugopalan B, Dominguez Gerpe L, Yeh HJ, Flippen-Anderson JL, Buchs P, Luo XD, Milhous W, Peters W.
Abstract : Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.
|
Intrinsic equimolar activity against Plasmodium falciparum W2 Indochina relative to QHS
|
Plasmodium falciparum
|
1.92
nM
|
|
Journal : J. Med. Chem.
Title : Arteether, a new antimalarial drug: synthesis and antimalarial properties.
Year : 1988
Volume : 31
Issue : 3
First Page : 645
Last Page : 650
Authors : Brossi A, Venugopalan B, Dominguez Gerpe L, Yeh HJ, Flippen-Anderson JL, Buchs P, Luo XD, Milhous W, Peters W.
Abstract : Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.
|
In vitro antimalarial activity against Plasmodium falciparum D6 (Sierra Leone I)
|
Plasmodium falciparum
|
0.0008689
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Antimalarial activity of new dihydroartemisinin derivatives. 6. alpha-Alkylbenzylic ethers.
Year : 1995
Volume : 38
Issue : 5
First Page : 764
Last Page : 770
Authors : Lin AJ, Miller RE.
Abstract : A series of diastereomeric dihydroartemisinin alpha-alkylbenzylic ethers was synthesized in search for analogs with higher antimalarial efficacy and longer plasma half-life than the existing artemisinin derivatives. Artelinic acid was used as the model molecule for the design of new analogs. Two approaches were taken in an attempt to (a) increase the lipophilicity of the molecule and (b) decrease the rate of oxidative dealkylation of the target compounds. All compounds in this study showed at least equal or better in vitro antimalarial activity against Plasmodium falciparum than artelinic acid. The most active compounds of this series showed 10-, 20-, and 40-fold better inhibitory activity than artemether, artemisinin, and artelinic acid, respectively. Compounds which have a small methyl group substituted at the alpha-methylene group showed weaker activity than compounds with a larger carbethoxyalkyl substituent, indicating that the lipophilicity and the steric effect of the molecules play important roles in their antimalarial activity. This fact is further substantiated by the significantly weaker antimalarial activity of the carboxylic acids than their corresponding esters. Compounds with electron-withdrawing function (NO2) substantially increase the antimalarial activity. The S-diastereomers, in general, are severalfold more potent than the corresponding R-isomer.
|
In vitro antimalarial activity against Plasmodium falciparum W2 Indochina
|
Plasmodium falciparum
|
0.0003008
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Antimalarial activity of new dihydroartemisinin derivatives. 6. alpha-Alkylbenzylic ethers.
Year : 1995
Volume : 38
Issue : 5
First Page : 764
Last Page : 770
Authors : Lin AJ, Miller RE.
Abstract : A series of diastereomeric dihydroartemisinin alpha-alkylbenzylic ethers was synthesized in search for analogs with higher antimalarial efficacy and longer plasma half-life than the existing artemisinin derivatives. Artelinic acid was used as the model molecule for the design of new analogs. Two approaches were taken in an attempt to (a) increase the lipophilicity of the molecule and (b) decrease the rate of oxidative dealkylation of the target compounds. All compounds in this study showed at least equal or better in vitro antimalarial activity against Plasmodium falciparum than artelinic acid. The most active compounds of this series showed 10-, 20-, and 40-fold better inhibitory activity than artemether, artemisinin, and artelinic acid, respectively. Compounds which have a small methyl group substituted at the alpha-methylene group showed weaker activity than compounds with a larger carbethoxyalkyl substituent, indicating that the lipophilicity and the steric effect of the molecules play important roles in their antimalarial activity. This fact is further substantiated by the significantly weaker antimalarial activity of the carboxylic acids than their corresponding esters. Compounds with electron-withdrawing function (NO2) substantially increase the antimalarial activity. The S-diastereomers, in general, are severalfold more potent than the corresponding R-isomer.
|
In vitro inhibition of chloroquine-resistant Plasmodium falciparum K1
|
Plasmodium falciparum
|
0.00074
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: charting a workable structure-activity relationship using simple prototypes.
Year : 2005
Volume : 48
Issue : 15
First Page : 4953
Last Page : 4961
Authors : Dong Y, Chollet J, Matile H, Charman SA, Chiu FC, Charman WN, Scorneaux B, Urwyler H, Santo Tomas J, Scheurer C, Snyder C, Dorn A, Wang X, Karle JM, Tang Y, Wittlin S, Brun R, Vennerstrom JL.
Abstract : This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure-activity relationship in the context of physicochemical, biopharmaceutical, and toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) in which the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified as a lead compound. Nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes without the spiroadamantane. The trioxolanes were substantially less effective in a standard oral suspension formulation compared to a solubilizing formulation and were more active when administered subcutaneously than orally, both of which suggest substantial biopharmaceutical liabilities. Nonetheless, despite their limited oral bioavailability, the more lipophilic trioxolanes generally had better oral activity than their more polar counterparts. In pharmacokinetic experiments, four trioxolanes had high plasma clearance values, suggesting a potential metabolic instability. The toxicological profiles of two trioxolanes were comparable to that of artesunate.
|
In vitro inhibition of chloroquine-sensitive Plasmodium falciparum NF54
|
Plasmodium falciparum
|
0.0012
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: charting a workable structure-activity relationship using simple prototypes.
Year : 2005
Volume : 48
Issue : 15
First Page : 4953
Last Page : 4961
Authors : Dong Y, Chollet J, Matile H, Charman SA, Chiu FC, Charman WN, Scorneaux B, Urwyler H, Santo Tomas J, Scheurer C, Snyder C, Dorn A, Wang X, Karle JM, Tang Y, Wittlin S, Brun R, Vennerstrom JL.
Abstract : This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure-activity relationship in the context of physicochemical, biopharmaceutical, and toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) in which the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified as a lead compound. Nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes without the spiroadamantane. The trioxolanes were substantially less effective in a standard oral suspension formulation compared to a solubilizing formulation and were more active when administered subcutaneously than orally, both of which suggest substantial biopharmaceutical liabilities. Nonetheless, despite their limited oral bioavailability, the more lipophilic trioxolanes generally had better oral activity than their more polar counterparts. In pharmacokinetic experiments, four trioxolanes had high plasma clearance values, suggesting a potential metabolic instability. The toxicological profiles of two trioxolanes were comparable to that of artesunate.
|
Antimalarial activity against Plasmodium falciparum K1
|
Plasmodium falciparum
|
0.00074
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antimalarial activity of N-alkyl amine, carboxamide, sulfonamide, and urea derivatives of a dispiro-1,2,4-trioxolane piperidine.
Year : 2006
Volume : 16
Issue : 21
First Page : 5542
Last Page : 5545
Authors : Padmanilayam M, Scorneaux B, Dong Y, Chollet J, Matile H, Charman SA, Creek DJ, Charman WN, Tomas JS, Scheurer C, Wittlin S, Brun R, Vennerstrom JL.
Abstract : With an aim to identify a dispiro-1,2,4-trioxolane with high oral activity and good physicochemical properties, 27 derivatives of an achiral piperidine trioxolane were synthesized; most were potent antimalarial peroxides with IC(50)s ranging from 0.20 to 7.0 ng/mL. The oral efficacies of two of these were superior to artesunate and comparable to artemether. The attractive chemical simplicity of these compounds is balanced only by an apparent metabolic susceptibility.
|
Antimalarial activity against Plasmodium falciparum NF54
|
Plasmodium falciparum
|
0.0012
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antimalarial activity of N-alkyl amine, carboxamide, sulfonamide, and urea derivatives of a dispiro-1,2,4-trioxolane piperidine.
Year : 2006
Volume : 16
Issue : 21
First Page : 5542
Last Page : 5545
Authors : Padmanilayam M, Scorneaux B, Dong Y, Chollet J, Matile H, Charman SA, Creek DJ, Charman WN, Tomas JS, Scheurer C, Wittlin S, Brun R, Vennerstrom JL.
Abstract : With an aim to identify a dispiro-1,2,4-trioxolane with high oral activity and good physicochemical properties, 27 derivatives of an achiral piperidine trioxolane were synthesized; most were potent antimalarial peroxides with IC(50)s ranging from 0.20 to 7.0 ng/mL. The oral efficacies of two of these were superior to artesunate and comparable to artemether. The attractive chemical simplicity of these compounds is balanced only by an apparent metabolic susceptibility.
|
Antimalarial activity against Plasmodium falciparum 3D7
|
Plasmodium falciparum
|
3.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : An efficient route into synthetically challenging bridged achiral 1,2,4,5-tetraoxanes with antimalarial activity.
Year : 2008
Volume : 18
Issue : 5
First Page : 1720
Last Page : 1724
Authors : Ellis GL, Amewu R, Hall C, Rimmer K, Ward SA, O'Neill PM.
Abstract : Here we present an efficient route into synthetically challenging bridged 1,2,4,5-tetraoxanes. The key to the success of this route is the use of H(2)O(2) and catalytic I(2) to form the gem-dihydroperoxide followed by a Ag(2)O mediated alkylation using 1,3-diiodopropane. Using this methodology a range of bridged tetraoxanes which display good in vitro antimalarial activity were synthesized.
|
Antiparasitic activity against chloroquine-sensitive Plasmodium falciparum by [3H]hypoxanthine incorporation
|
Plasmodium falciparum
|
2.8
nM
|
|
Journal : J. Med. Chem.
Title : Antimalarial dual drugs based on potent inhibitors of glutathione reductase from Plasmodium falciparum.
Year : 2008
Volume : 51
Issue : 5
First Page : 1260
Last Page : 1277
Authors : Friebolin W, Jannack B, Wenzel N, Furrer J, Oeser T, Sanchez CP, Lanzer M, Yardley V, Becker K, Davioud-Charvet E.
Abstract : Plasmodium parasites are exposed to higher fluxes of reactive oxygen species and need high activities of intracellular antioxidant systems providing a steady glutathione flux. As a future generation of dual drugs, 18 naphthoquinones and phenols (or their reduced forms) containing three different linkers between the 4-aminoquinoline core and the redox active component were synthesized. Their antimalarial effects have been characterized in parasite assays using chloroquine-sensitive and -resistant strains of Plasmodium, alone or in drug combination, and in the Plasmodium berghei rodent model. In particular, two tertiary amides 34 and 36 showed potent antimalarial activity in the low nanomolar range against CQ-resistant parasites. The ability to compete both for (Fe (III))protoporphyrin and for chloroquine transporter was determined. The data are consistent with the presence of a carrier for uptake of the short chloroquine analogue 2 but not for the potent antimalarial amide 34, suggesting a mode of action distinct from chloroquine mechanism.
|
Antimalarial activity against Plasmodium falciparum 3D7
|
Plasmodium falciparum
|
3.2
nM
|
|
Journal : J. Med. Chem.
Title : Two-step synthesis of achiral dispiro-1,2,4,5-tetraoxanes with outstanding antimalarial activity, low toxicity, and high-stability profiles.
Year : 2008
Volume : 51
Issue : 7
First Page : 2170
Last Page : 2177
Authors : Ellis GL, Amewu R, Sabbani S, Stocks PA, Shone A, Stanford D, Gibbons P, Davies J, Vivas L, Charnaud S, Bongard E, Hall C, Rimmer K, Lozanom S, Jesús M, Gargallo D, Ward SA, O'Neill PM.
Abstract : A rapid, two-step synthesis of a range of dispiro-1,2,4,5-tetraoxanes with potent antimalarial activity both in vitro and in vivo has been achieved. These 1,2,4,5-tetraoxanes have been proven to be superior to 1,2,4-trioxolanes in terms of stability and to be superior to trioxane analogues in terms of both stability and activity. Selected analogues have in vitro nanomolar antimalarial activity and good oral activity and are nontoxic in screens for both cytotoxicity and genotoxicity. The synthesis of a fluorescent 7-nitrobenza-2-oxa-1,3-diazole (NBD) tagged tetraoxane probe and use of laser scanning confocal microscopy techniques have shown that tagged molecules accumulate selectively only in parasite infected erythrocytes and that intraparasitic formation of adducts could be inhibited by co-incubation with the iron chelator desferrioxamine (DFO).
|
Antimalarial activity against Plasmodium falciparum 3D7 infected human erythrocytes after 24 hrs by [3H]hypoxanthine uptake
|
Plasmodium falciparum 3D7
|
1.26
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Piperidine dispiro-1,2,4-trioxane analogues.
Year : 2008
Volume : 18
Issue : 21
First Page : 5804
Last Page : 5804
Authors : Sabbani S, Stocks PA, Ellis GL, Davies J, Hedenstrom E, Ward SA, O'Neill PM.
Abstract : Dispiro N-Boc-protected 1,2,4-trioxane 2 was synthesised via Mo(acac)(2) catalysed perhydrolysis of N-Boc spirooxirane followed by condensation of the resulting beta-hydroperoxy alcohol 10 with 2-adamantanone. N-Boc 1,2,4-trioxane 2 was converted to the amine 1,2,4-trioxane hydrochloride salt 3 which was subsequently used to prepare derivatives (4-7). Several of these novel 1,2,4-trioxanes had nanomolar antimalarial activity versus the 3D7 strain of Plasmodium falciparum. Amine intermediate 3 represents a versatile derivative for the preparation of achiral arrays of trioxane analogues with antimalarial activity.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum K1 by [3H]hypoxanthine uptake
|
Plasmodium falciparum
|
3.53
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of extraordinarily potent C-10 carba artemisinin dimers against P. falciparum malaria parasites and HL-60 cancer cells.
Year : 2009
Volume : 17
Issue : 3
First Page : 1325
Last Page : 1338
Authors : Chadwick J, Chadwick J, Mercer AE, Park BK, Cosstick R, O'Neill PM.
Abstract : A series of artemisinin dimers incorporating a metabolically stable C-10 carba-linkage have been prepared, several of which show remarkable in vitro antimalarial activity (as low as 30 pM) versus Plasmodium falciparum and in vitro anticancer activity in the micromolar to nanomolar range versus HL-60 cell lines.
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum 3D7 by [3H]hypoxanthine uptake
|
Plasmodium falciparum 3D7
|
2.11
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of extraordinarily potent C-10 carba artemisinin dimers against P. falciparum malaria parasites and HL-60 cancer cells.
Year : 2009
Volume : 17
Issue : 3
First Page : 1325
Last Page : 1338
Authors : Chadwick J, Chadwick J, Mercer AE, Park BK, Cosstick R, O'Neill PM.
Abstract : A series of artemisinin dimers incorporating a metabolically stable C-10 carba-linkage have been prepared, several of which show remarkable in vitro antimalarial activity (as low as 30 pM) versus Plasmodium falciparum and in vitro anticancer activity in the micromolar to nanomolar range versus HL-60 cell lines.
|
Antifungal activity against Cryptococcus neoformans ATCC 90113 by modified NCCLS method
|
Cryptococcus neoformans
|
0.6
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Antifungal activity of artemisinin derivatives.
Year : 2005
Volume : 68
Issue : 8
First Page : 1274
Last Page : 1276
Authors : Galal AM, Ross SA, Jacob M, ElSohly MA.
Abstract : A series of 29 artemisinin derivatives (2-30), including four new compounds (16-18, 20), together with artemisinin (1), artemisinic acid (31), and arteannuin B (32), were tested for antifungal activity against two opportunistic pathogens, Candida albicans and Cryptoccocus neoformans. Of all the compounds tested, anhydrodihydro-artemisinin (3) demonstrated more potent antifungal activity against C. neoformans than amphotericin B. Also, beta-arteether (7) and alpha-arteether (8) showed marked activity against C. neoformans. Against C. albicans, the overall antifungal effect of these compounds was weak or negligible. Derivatives 2-30 were prepared according to literature procedures.
|
Antimalarial activity after 48 hrs against chloroquine-sensitive Plasmodium falciparum 3D7 by [3H]hypoxanthine uptake
|
Plasmodium falciparum 3D7
|
3.53
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antitumour and antimalarial activity of artemisinin-acridine hybrids.
Year : 2009
Volume : 19
Issue : 7
First Page : 2033
Last Page : 2037
Authors : Jones M, Mercer AE, Stocks PA, La Pensée LJ, Cosstick R, Park BK, Kennedy ME, Piantanida I, Ward SA, Davies J, Bray PG, Rawe SL, Baird J, Charidza T, Janneh O, O'Neill PM.
Abstract : Artemisinin-acridine hybrids were prepared and evaluated for their in vitro activity against tumour cell lines and a chloroquine sensitive strain of Plasmodium falciparum. They showed a 2-4-fold increase in activity against HL60, MDA-MB-231 and MCF-7 cells in comparison with dihydroartemisinin (DHA) and moderate antimalarial activity. Strong evidence that the compounds induce apoptosis in HL60 cells was obtained by flow cytometry, which indicated accumulation of cells in the G1 phase of the cell cycle.
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum 3D7 infected type A+ human erythrocytes after 24 hrs by [G-3H]hypoxanthine uptake
|
Plasmodium falciparum 3D7
|
3.45
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Semi-synthetic and synthetic 1,2,4-trioxaquines and 1,2,4-trioxolaquines: synthesis, preliminary SAR and comparison with acridine endoperoxide conjugates.
Year : 2009
Volume : 19
Issue : 7
First Page : 2038
Last Page : 2043
Authors : Araújo NC, Barton V, Jones M, Stocks PA, Ward SA, Davies J, Bray PG, Shone AE, Cristiano ML, O'Neill PM.
Abstract : A novel series of semi-synthetic trioxaquines and synthetic trioxolaquines were prepared, in moderate to good yields. Antimalarial activity was evaluated against both the chloroquine-sensitive 3D7 and resistant K1 strain of Plasmodium falciparum and both series of compounds were shown to be active in the low nanomolar range. For comparison the corresponding 9-amino acridine analogues were also prepared and shown to have low nanomolar activity like their quinoline counterparts.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum K1 infected type A+ human erythrocytes after 24 hrs by [G-3H]hypoxanthine uptake
|
Plasmodium falciparum K1
|
1.26
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Semi-synthetic and synthetic 1,2,4-trioxaquines and 1,2,4-trioxolaquines: synthesis, preliminary SAR and comparison with acridine endoperoxide conjugates.
Year : 2009
Volume : 19
Issue : 7
First Page : 2038
Last Page : 2043
Authors : Araújo NC, Barton V, Jones M, Stocks PA, Ward SA, Davies J, Bray PG, Shone AE, Cristiano ML, O'Neill PM.
Abstract : A novel series of semi-synthetic trioxaquines and synthetic trioxolaquines were prepared, in moderate to good yields. Antimalarial activity was evaluated against both the chloroquine-sensitive 3D7 and resistant K1 strain of Plasmodium falciparum and both series of compounds were shown to be active in the low nanomolar range. For comparison the corresponding 9-amino acridine analogues were also prepared and shown to have low nanomolar activity like their quinoline counterparts.
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum 3D7 assessed as growth inhibition by [3H]hypoxanthine incorporation assay
|
Plasmodium falciparum
|
4.2
nM
|
|
Journal : J. Med. Chem.
Title : Modular synthesis and in vitro and in vivo antimalarial assessment of C-10 pyrrole mannich base derivatives of artemisinin.
Year : 2010
Volume : 53
Issue : 2
First Page : 633
Last Page : 640
Authors : Pacorel B, Leung SC, Stachulski AV, Davies J, Vivas L, Lander H, Ward SA, Kaiser M, Brun R, O'Neill PM.
Abstract : In two steps from dihydroartemisinin, a small array of 16 semisynthetic C-10 pyrrole Mannich artemisinin derivatives (7a-p) have been prepared in moderate to excellent yield. In vitro analysis against both chloroquine sensitive and resistant strains has demonstrated that these analogues have nanomolar antimalarial activity, with several compounds being more than 3 times more potent than the natural product artemisinin. In addition to a potent antimalarial profile, these molecules also have very high in vitro therapeutic indices. Analysis of the optimal Mannich side chain substitution for in vitro and in vivo activity reveals that the morpholine and N-methylpiperazine Mannich side chains provide analogues with the best activity profiles, both in vitro and in vivo in the Peter's 4 day test.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum K1 (Thailand) assessed as growth inhibition by [3H]hypoxanthine incorporation assay
|
Plasmodium falciparum K1
|
3.4
nM
|
|
Journal : J. Med. Chem.
Title : Modular synthesis and in vitro and in vivo antimalarial assessment of C-10 pyrrole mannich base derivatives of artemisinin.
Year : 2010
Volume : 53
Issue : 2
First Page : 633
Last Page : 640
Authors : Pacorel B, Leung SC, Stachulski AV, Davies J, Vivas L, Lander H, Ward SA, Kaiser M, Brun R, O'Neill PM.
Abstract : In two steps from dihydroartemisinin, a small array of 16 semisynthetic C-10 pyrrole Mannich artemisinin derivatives (7a-p) have been prepared in moderate to excellent yield. In vitro analysis against both chloroquine sensitive and resistant strains has demonstrated that these analogues have nanomolar antimalarial activity, with several compounds being more than 3 times more potent than the natural product artemisinin. In addition to a potent antimalarial profile, these molecules also have very high in vitro therapeutic indices. Analysis of the optimal Mannich side chain substitution for in vitro and in vivo activity reveals that the morpholine and N-methylpiperazine Mannich side chains provide analogues with the best activity profiles, both in vitro and in vivo in the Peter's 4 day test.
|
Antimalarial activity against Plasmodium berghei ANKA infected Swiss CD1 mice (Mus musculus) assessed as reduction of parasitemia at 30 mg/kg, perorally administered after 3 hrs of infection for 3 days measured on day 4 relative to control
|
Plasmodium berghei
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Modular synthesis and in vitro and in vivo antimalarial assessment of C-10 pyrrole mannich base derivatives of artemisinin.
Year : 2010
Volume : 53
Issue : 2
First Page : 633
Last Page : 640
Authors : Pacorel B, Leung SC, Stachulski AV, Davies J, Vivas L, Lander H, Ward SA, Kaiser M, Brun R, O'Neill PM.
Abstract : In two steps from dihydroartemisinin, a small array of 16 semisynthetic C-10 pyrrole Mannich artemisinin derivatives (7a-p) have been prepared in moderate to excellent yield. In vitro analysis against both chloroquine sensitive and resistant strains has demonstrated that these analogues have nanomolar antimalarial activity, with several compounds being more than 3 times more potent than the natural product artemisinin. In addition to a potent antimalarial profile, these molecules also have very high in vitro therapeutic indices. Analysis of the optimal Mannich side chain substitution for in vitro and in vivo activity reveals that the morpholine and N-methylpiperazine Mannich side chains provide analogues with the best activity profiles, both in vitro and in vivo in the Peter's 4 day test.
|
Antiparasitic activity against Toxoplasma gondii 2F infected in HFF cells assessed as beta galactosidase activity after 5 days
|
Toxoplasma gondii
|
310.0
nM
|
|
Journal : J. Med. Chem.
Title : Thiazole, oxadiazole, and carboxamide derivatives of artemisinin are highly selective and potent inhibitors of Toxoplasma gondii.
Year : 2010
Volume : 53
Issue : 9
First Page : 3594
Last Page : 3601
Authors : Hencken CP, Jones-Brando L, Bordón C, Stohler R, Mott BT, Yolken R, Posner GH, Woodard LE.
Abstract : We have prepared 23 new dehydroartemisinin (DART) trioxane derivatives (11 thiazoles, 2 oxadiazoles, and 10 carboxamides) and have screened them for in vitro activity in the Toxoplasma lytic cycle. Fifteen (65%) of the derivatives were noncytotoxic to host cells (TD(50) > or = 320 microM). Eight thiazole derivatives and two carboxamide derivatives displayed effective inhibition of Toxoplasma growth (IC(50) = 0.25-0.42 microM), comparable in potency to artemether (IC(50) = 0.31 microM) and >100 times more inhibitory than the currently employed front-line drug trimethoprim (IC(50) = 46 microM). The thiazoles as a group were more effective than the other derivatives at inhibiting growth of extracellular as well as intracellular parasites. Unexpectedly, two thiazole trioxanes (5 and 6) were parasiticidal; both inhibited parasite replication irreversibly after parasite exposure to 10 microM of drug for 24 h, whereas the standard trioxane drugs artemisinin and artemether were not parasiticidal. Some of the new derivatives of artemisinin described here represent effective anti-Toxoplasma trioxanes as well as molecular probes for elucidating the mechanism of action of the DART class of artemisinin derivatives.
|
Antimalarial activity against Plasmodium falciparum 3D7 assessed as parasite growth inhibition at 8 nM after 6 hrs by [3H]hypoxanthin incorporation assay
|
Plasmodium falciparum
|
90.0
%
|
|
Journal : Science
Title : Spiroindolones, a potent compound class for the treatment of malaria.
Year : 2010
Volume : 329
Issue : 5996
First Page : 1175
Last Page : 1180
Authors : Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT.
Abstract : Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
|
Induction of heme alkylation of Fe(II) heme assessed as loss of heme at 10 uM in presence of 50% ACN-H2O with excess sodium dithionite under argon at 20 degC by spectrophotometry
|
None
|
24.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Relationship between antimalarial activity and heme alkylation for spiro- and dispiro-1,2,4-trioxolane antimalarials.
Year : 2008
Volume : 52
Issue : 4
First Page : 1291
Last Page : 1296
Authors : Creek DJ, Charman WN, Chiu FC, Prankerd RJ, Dong Y, Vennerstrom JL, Charman SA.
Abstract : The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarials with heme has been investigated to provide further insight into the mechanism of action for this important class of antimalarials. A series of trioxolanes with various antimalarial potencies was found to be unreactive in the presence of Fe(III) hemin, but all were rapidly degraded by reduced Fe(II) heme. The major reaction product from the heme-mediated degradation of biologically active trioxolanes was an alkylated heme adduct resulting from addition of a radical intermediate. Under standardized reaction conditions, a correlation (R2 = 0.88) was found between the extent of heme alkylation and in vitro antimalarial activity, suggesting that heme alkylation may be related to the mechanism of action for these trioxolanes. Significantly less heme alkylation was observed for the clinically utilized artemisinin derivatives compared to the equipotent trioxolanes included in this study.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum K1
|
Plasmodium falciparum K1
|
2.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Relationship between antimalarial activity and heme alkylation for spiro- and dispiro-1,2,4-trioxolane antimalarials.
Year : 2008
Volume : 52
Issue : 4
First Page : 1291
Last Page : 1296
Authors : Creek DJ, Charman WN, Chiu FC, Prankerd RJ, Dong Y, Vennerstrom JL, Charman SA.
Abstract : The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarials with heme has been investigated to provide further insight into the mechanism of action for this important class of antimalarials. A series of trioxolanes with various antimalarial potencies was found to be unreactive in the presence of Fe(III) hemin, but all were rapidly degraded by reduced Fe(II) heme. The major reaction product from the heme-mediated degradation of biologically active trioxolanes was an alkylated heme adduct resulting from addition of a radical intermediate. Under standardized reaction conditions, a correlation (R2 = 0.88) was found between the extent of heme alkylation and in vitro antimalarial activity, suggesting that heme alkylation may be related to the mechanism of action for these trioxolanes. Significantly less heme alkylation was observed for the clinically utilized artemisinin derivatives compared to the equipotent trioxolanes included in this study.
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum 3D7 after 72 hrs by MSF assay
|
Plasmodium falciparum
|
0.0004
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Coumarin-trioxane hybrids: synthesis and evaluation as a new class of antimalarial scaffolds.
Year : 2012
Volume : 22
Issue : 12
First Page : 3926
Last Page : 3930
Authors : Sashidhara KV, Kumar A, Dodda RP, Krishna NN, Agarwal P, Srivastava K, Puri SK.
Abstract : First synthesis of novel coumarin-trioxane hybrids is reported. The synthesis was achieved via condensation of β-hydroxyhydroperoxides with coumarinic-aldehydes in presence of p-toluenesulfonic acid in good yields and the novel hybrids were evaluated for their antimalarial activity both in vitro and in vivo.
|
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.
|
Antiplasmodial activity against Plasmodium berghei ANKA early trophozoite stage by parasite LDH assay
|
Plasmodium berghei ANKA
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : NO-Donor Dihydroartemisinin Derivatives as Multitarget Agents for the Treatment of Cerebral Malaria.
Year : 2015
Volume : 58
Issue : 19
First Page : 7895
Last Page : 7899
Authors : Bertinaria M, Orjuela-Sanchez P, Marini E, Guglielmo S, Hofer A, Martins YC, Zanini GM, Frangos JA, Gasco A, Fruttero R, Carvalho LJ.
Abstract : Hybrid products in which the dihydroartemisinin scaffold is combined with NO-donor furoxan and NONOate moieties have been synthesized and studied as potential tools for the treatment of cerebral malaria (CM). The designed products were able to dilate rat aorta strips precontracted with phenylephrine with a NO-dependent mechanism. All hybrid compounds showed preserved antiplasmodial activity in vitro and in vivo against Plasmodium berghei ANKA, comparable to artesunate and artemether. Hybrid 10, selected for additional studies, was capable of increasing survival of mice with late-stage CM from 27.5% to 51.6% compared with artemether. Artemisinin-NO-donor hybrid compounds show promise as potential new drugs for treating cerebral malaria.
|
Antimalarial activity against chloroquine-sensitive asexual Plasmodium falciparum NF54 infected in human erythrocytes assessed as inhibition of parasite proliferation after 96 hrs by SYBR Green I fluorescence based assay
|
Plasmodium falciparum NF54
|
5.77
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities.
Year : 2016
Volume : 26
Issue : 13
First Page : 3006
Last Page : 3009
Authors : Beteck RM, Coertzen D, Smit FJ, Birkholtz LM, Haynes RK, N'Da DD.
Abstract : As part of a programme aimed at identifying rational new triple drug combinations for treatment of malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that selected examples exhibit exceptionally good activities against the causative pathogens of the foregoing diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the other accessible and active derivatives serve as an attractive template for development of new and economic lead quinolones.
|
Antimalarial activity against multidrug resistant Plasmodium falciparum K1 infected in human erythrocytes assessed as inhibition of parasite proliferation after 96 hrs by SYBR Green I fluorescence based assay
|
Plasmodium falciparum K1
|
7.26
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities.
Year : 2016
Volume : 26
Issue : 13
First Page : 3006
Last Page : 3009
Authors : Beteck RM, Coertzen D, Smit FJ, Birkholtz LM, Haynes RK, N'Da DD.
Abstract : As part of a programme aimed at identifying rational new triple drug combinations for treatment of malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that selected examples exhibit exceptionally good activities against the causative pathogens of the foregoing diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the other accessible and active derivatives serve as an attractive template for development of new and economic lead quinolones.
|
Antimalarial activity against multidrug resistant Plasmodium falciparum W2 infected in human erythrocytes assessed as inhibition of parasite proliferation after 96 hrs by SYBR Green I fluorescence based assay
|
Plasmodium falciparum
|
4.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities.
Year : 2016
Volume : 26
Issue : 13
First Page : 3006
Last Page : 3009
Authors : Beteck RM, Coertzen D, Smit FJ, Birkholtz LM, Haynes RK, N'Da DD.
Abstract : As part of a programme aimed at identifying rational new triple drug combinations for treatment of malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that selected examples exhibit exceptionally good activities against the causative pathogens of the foregoing diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the other accessible and active derivatives serve as an attractive template for development of new and economic lead quinolones.
|
Antiplasmodial activity against chloroquine-sensitive asexual erythrocyte stage form Plasmodium falciparum NF54 measured after 48 hrs by pLDH assay
|
Plasmodium falciparum NF54
|
3.8
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of a series of non-hemiacetal ester derivatives of artemisinin.
Year : 2016
Volume : 122
First Page : 635
Last Page : 646
Authors : Zuma NH, Smit FJ, de Kock C, Combrinck J, Smith PJ, N'Da DD.
Abstract : In an attempt to improve the efficacy and stability of current, clinically used artemisinins, a series non-hemiacetal ester derivatives of artemisinin were synthesized and evaluated for their in vitro antiplasmodial and anticancer activities as well as cytotoxicities. These esters were synthesized through the reaction of acid anhydrides, or acid chlorides with artemisinin derived alcohol. In vitro antiplasmodial activity assessments were conducted against intraerythrocytic NF54 and Dd2 Plasmodium falciparum strains. Cytotoxicities were assessed, using normal human fetal lung fibroblast (WI-38) and Chinese hamster ovarian (CHO) mammalian cell lines, while anticancer activities were tested by using panels with three cell lines, consisting of renal (TK10), melanoma (UACC62) and breast (MCF7) cancer cells. Most compounds were found active against the breast cancer cell line. Since antiplasmodial activities for most compounds were found comparable only to that of artesunate, this study did not yield any esters with significantly improved antimalarial efficacies, nor did it deliver any promising antitumor hits. However, from the outcomes of this study, compounds with good safety profiles and increased thermal stabilities, compared to the clinically used artemisinins, were identified. The benzoate derivative 11 was found to have antimalarial activity, comparable to that of dihydroartemisinin and was it subsequently identified as a candidate for further investigation in the urgent search for new, safe and effective antimalarial drugs.
|
Antiplasmodial activity against chloroquine-resistant asexual erythrocyte stage form Plasmodium falciparum Dd2 measured after 48 hrs by pLDH assay
|
Plasmodium falciparum Dd2
|
2.3
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of a series of non-hemiacetal ester derivatives of artemisinin.
Year : 2016
Volume : 122
First Page : 635
Last Page : 646
Authors : Zuma NH, Smit FJ, de Kock C, Combrinck J, Smith PJ, N'Da DD.
Abstract : In an attempt to improve the efficacy and stability of current, clinically used artemisinins, a series non-hemiacetal ester derivatives of artemisinin were synthesized and evaluated for their in vitro antiplasmodial and anticancer activities as well as cytotoxicities. These esters were synthesized through the reaction of acid anhydrides, or acid chlorides with artemisinin derived alcohol. In vitro antiplasmodial activity assessments were conducted against intraerythrocytic NF54 and Dd2 Plasmodium falciparum strains. Cytotoxicities were assessed, using normal human fetal lung fibroblast (WI-38) and Chinese hamster ovarian (CHO) mammalian cell lines, while anticancer activities were tested by using panels with three cell lines, consisting of renal (TK10), melanoma (UACC62) and breast (MCF7) cancer cells. Most compounds were found active against the breast cancer cell line. Since antiplasmodial activities for most compounds were found comparable only to that of artesunate, this study did not yield any esters with significantly improved antimalarial efficacies, nor did it deliver any promising antitumor hits. However, from the outcomes of this study, compounds with good safety profiles and increased thermal stabilities, compared to the clinically used artemisinins, were identified. The benzoate derivative 11 was found to have antimalarial activity, comparable to that of dihydroartemisinin and was it subsequently identified as a candidate for further investigation in the urgent search for new, safe and effective antimalarial drugs.
|
Antiplasmodial activity against chloroquine-resistant Plasmodium falciparum K1 infected in human O-positive erythrocytes assessed as decrease in parasitaemia after 72 hrs by NBT dye-based spectrophotometric method
|
Plasmodium falciparum K1
|
20.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel triazine dimers with potent antitrypanosomal activity.
Year : 2018
Volume : 143
First Page : 306
Last Page : 319
Authors : Venkatraj M, Salado IG, Heeres J, Joossens J, Lewi PJ, Caljon G, Maes L, Van der Veken P, Augustyns K.
Abstract : Human African trypanosomiasis (HAT), also known as sleeping sickness is a parasitic disease transmitted by the bite of the 'Glossina' insect, commonly known as the tsetse fly. This disease affects mostly poor populations living in remote rural areas of Africa. Untreated, it is usually fatal. Currently, safe and effective treatments against this disease are lacking. Phenotypic screening of triazine non-nucleoside HIV-1 reverse transcriptase inhibitors (monomers) resulted in potent and selective antitrypanosomal compounds. This serendipitous discovery and the presence of dimers in many compounds active against these neglected tropical diseases prompted us to investigate antitrypanosomal activity of triazine dimers. Optimization of the triazine dimers resulted in 3,3'-(((ethane-1,2-diylbis(azanediyl))bis(4-(mesityloxy)-1,3,5-triazine-6,2-diyl))bis(azanediyl))dibenzonitrile (compound 38), a compound with very potent in vitro and moderate in vivo antitrypanosomal activity.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
8.78
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
13.66
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
9.17
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
12.03
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
30.63
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
19.11
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
6.04
%
|
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
8.42
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
3.43
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
23.59
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.09
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.34
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.09
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.34
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Antiplasmodial activity against chloroquine-sensitive Plasmodium falciparum NF54 by LDH assay
|
Plasmodium falciparum
|
3.8
nM
|
|
Journal : Bioorg Med Chem Lett
Title : In vitro efficacy of synthesized artemisinin derivatives against Leishmania promastigotes.
Year : 2020
Volume : 30
Issue : 22
First Page : 127581
Last Page : 127581
Authors : Aucamp J,Zuma NH,N'Da DD
Abstract : Leishmaniasis is a neglected tropical disease affecting thousands worldwide, especially in developing countries where it co-exists with malaria. Only a handful of drugs are clinically available to treat the disease, but significant limitations threaten their very use. New, safe and effective drugs, including those against malaria-leishmaniasis co-infections, are thus imperative. We assessed the in vitro anti-infective potential of previously synthesized, potent antimalarial artemisinin derivatives. Analogue esters featuring 1,1'-biphenyl and thiophenyl moieties were as much as 30-fold more potent than clinical artemisinins against L. donovani parasites, qualifying them as antipromastigote hits for further investigation in the search for malaria-leishmaniasis co-infection therapies.
|
Antiplasmodial activity against chloroquine-resistant Plasmodium falciparum Dd2 by LDH assay
|
Plasmodium falciparum
|
2.3
nM
|
|
Journal : Bioorg Med Chem Lett
Title : In vitro efficacy of synthesized artemisinin derivatives against Leishmania promastigotes.
Year : 2020
Volume : 30
Issue : 22
First Page : 127581
Last Page : 127581
Authors : Aucamp J,Zuma NH,N'Da DD
Abstract : Leishmaniasis is a neglected tropical disease affecting thousands worldwide, especially in developing countries where it co-exists with malaria. Only a handful of drugs are clinically available to treat the disease, but significant limitations threaten their very use. New, safe and effective drugs, including those against malaria-leishmaniasis co-infections, are thus imperative. We assessed the in vitro anti-infective potential of previously synthesized, potent antimalarial artemisinin derivatives. Analogue esters featuring 1,1'-biphenyl and thiophenyl moieties were as much as 30-fold more potent than clinical artemisinins against L. donovani parasites, qualifying them as antipromastigote hits for further investigation in the search for malaria-leishmaniasis co-infection therapies.
|
Antifungal activity against Candida albicans SC5314 assessed as inhibition of fungal growth by measuring decrease in OD600 at 100 microM measured after 24 hrs by absorbance based analysis
|
Candida albicans
|
10.1
%
|
|
|
Antifungal activity against Saccharomyces cerevisiae BY4742 assessed as inhibition of fungal growth at 100 uM measured after 24 hrs by absorbance based analysis relative to vehicle-treated control
|
Saccharomyces cerevisiae
|
45.8
%
|
|
|
Potentiation of fluconazole-induced antifungal activity against Saccharomyces cerevisiae BY4742 assessed as inhibition of fungal growth at 100 uM measured after 24 hrs in presence of fluconazole by absorbance based analysis relative to fluconazole-treated control
|
Saccharomyces cerevisiae
|
68.8
%
|
|
