SPERGUALIN


Synonyms	Antibiotic bmg 162af2 Antibiotic bmg-162af2 Ls-74246 Spergualin
Status
Molecule Category	UNKNOWN
UNII	987K1SBI71
EPA CompTox	DTXSID30432754


Active Pharmaceutical Ingredients Bioactive chemicals	Exact Similarity SubStructure	Threshold (%) >= 70

Structure


InChI Key	NXLUTEDAEFXMQR-BJKOFHAPSA-N
Smiles	O=C(N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(Cl)cc2)C1)c1ccnc2ccccc12
InChI	InChI=1S/C31H24ClF6N3O2/c32-22-7-5-18(6-8-22)13-24-17-23(40-28(42)26-9-11-39-27-4-2-1-3-25(26)27)10-12-41(24)29(43)19-14-20(30(33,34)35)16-21(15-19)31(36,37)38/h1-9,11,14-16,23-24H,10,12-13,17H2,(H,40,42)/t23-,24+/m0/s1

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C31H24ClF6N3O2
Molecular Weight	619.99
AlogP	7.57
Hydrogen Bond Acceptor	3.0
Hydrogen Bond Donor	1.0
Number of Rotational Bond	5.0
Polar Surface Area	62.3
Molecular species	NEUTRAL
Aromatic Rings	4.0
Heavy Atoms	43.0

Reference

Journal : Bioorg. Med. Chem.

Title : Non-peptide NK1 receptor ligands based on the 4-phenylpyridine moiety.

PubMed ID : 21421318

DOI : 10.1016/j.bmc.2011.02.031

Year : 2011

Volume : 19

Issue : 7

First Page : 2242

Last Page : 2251

Authors : Giuliani G, Cappelli A, Matarrese M, Masiello V, Turolla EA, Monterisi C, Fazio F, Anzini M, Pericot Mohr G, Riitano D, Finetti F, Morbidelli L, Ziche M, Giorgi G, Vomero S.

Abstract : The quinoline nucleus of the previously described 4-phenylquinoline-3-carboxamides NK(1) receptor ligands 7 has been transformed into either substituted or azole-(i.e., triazole or tetrazole) fused pyridine moieties of compounds 9 and 10, respectively, in order to obtain NK(1) receptor ligands showing lower molecular weight or higher hydrophilicity. The program of molecular manipulations produced NK(1) receptor ligands showing affinity in the nanomolar range. In particular, 4-methyl-1-piperazinyl derivative 9j showed an IC(50) value of 4.8 nM and was proved to behave as a NK(1) antagonist blocking Sar(9)-SP-sulfone induced proliferation and migration of microvascular endothelial cells. Therefore, compound 9j has been labeled with [(11)C]CH(3)I (t(1/2)=20.4 min, β(+)=99.8%) starting from the corresponding des-methyl precursor 9i using with a radiochemical yield of about 10% (not decay corrected) and a specific radioactivity>1 Ci/μmol in order to be used as a radiotracer in next PET studies.

Reference

Journal : Bioorg. Med. Chem.

Title : Non-peptide NK1 receptor ligands based on the 4-phenylpyridine moiety.

PubMed ID : 21421318

DOI : 10.1016/j.bmc.2011.02.031

Year : 2011

Volume : 19

Issue : 7

First Page : 2242

Last Page : 2251

Authors : Giuliani G, Cappelli A, Matarrese M, Masiello V, Turolla EA, Monterisi C, Fazio F, Anzini M, Pericot Mohr G, Riitano D, Finetti F, Morbidelli L, Ziche M, Giorgi G, Vomero S.

Reference

Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection

DOI : 10.21203/rs.3.rs-23951/v1

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.

Reference

Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen

DOI : 10.6019/CHEMBL4495564

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.

Reference

Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort

DOI : 10.6019/CHEMBL4495565

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.

Assay Description	Organism	Bioactivity
Binding affinity to gerbil NK1 receptor	Meriones unguiculatus	12.59 nM
Binding affinity to human NK1 receptor	Homo sapiens	0.07943 nM
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	34.39 %
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate	Severe acute respiratory syndrome coronavirus 2	16.67 %
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	-0.07 %	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	-0.07 %

Cross References

Resources	Reference
ChEMBL	CHEMBL1765508
FDA SRS	987K1SBI71
PubChem	15916864
SureChEMBL	SCHEMBL155207
ZINC	ZINC000003946509

CONTENTS

Structure
Chemical and Physical Properties