PYROXAMIDE


Synonyms	Octanedioic acid hydroxyamide pyridin-3-ylamide Pyroxamide
Status
Molecule Category	UNKNOWN
UNII	12N86DSS23
EPA CompTox	DTXSID70191595


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

Structure


InChI Key	PTJGLFIIZFVFJV-UHFFFAOYSA-N
Smiles	O=C(CCCCCCC(=O)Nc1cccnc1)NO
InChI	InChI=1S/C13H19N3O3/c17-12(15-11-6-5-9-14-10-11)7-3-1-2-4-8-13(18)16-19/h5-6,9-10,19H,1-4,7-8H2,(H,15,17)(H,16,18)

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C13H19N3O3
Molecular Weight	265.31
AlogP	1.87
Hydrogen Bond Acceptor	4.0
Hydrogen Bond Donor	3.0
Number of Rotational Bond	8.0
Polar Surface Area	91.32
Molecular species	NEUTRAL
Aromatic Rings	1.0
Heavy Atoms	19.0

Reference

Journal : J. Med. Chem.

Title : Inhibitors of human histone deacetylase: synthesis and enzyme and cellular activity of straight chain hydroxamates.

PubMed ID : 11831887

DOI : 10.1021/jm015568c

Year : 2002

Volume : 45

Issue : 4

First Page : 753

Last Page : 757

Authors : Remiszewski SW, Sambucetti LC, Atadja P, Bair KW, Cornell WD, Green MA, Howell KL, Jung M, Kwon P, Trogani N, Walker H.

Abstract : Inhibitors of histone deacetylase (HDAC) have been shown to induce terminal differentiation of human tumor cell lines and to have antitumor effects in vivo. We have prepared analogues of suberoylanilide hydroxamic acid (SAHA) and trichostatin A and have evaluated them in a human HDAC enzyme inhibition assay, a p21(waf1) (p21) promoter assay, and in monolayer growth inhibition assays. One compound, 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-benzamide, was found to affect the growth of a panel of eight human tumor cell lines differentially.

Reference

Journal : Nat. Chem. Biol.

Title : Chemical phylogenetics of histone deacetylases.

PubMed ID : 20139990

DOI : 10.1038/nchembio.313

Year : 2010

Volume : 6

Issue : 3

First Page : 238

Last Page : 243

Authors : Bradner JE, West N, Grachan ML, Greenberg EF, Haggarty SJ, Warnow T, Mazitschek R.

Abstract : The broad study of histone deacetylases in chemistry, biology and medicine relies on tool compounds to derive mechanistic insights. A phylogenetic analysis of class I and II histone deacetylases (HDACs) as targets of a comprehensive, structurally diverse panel of inhibitors revealed unexpected isoform selectivity even among compounds widely perceived as nonselective. The synthesis and study of a focused library of cinnamic hydroxamates allowed the identification of, to our knowledge, the first nonselective HDAC inhibitor. These data will guide a more informed use of HDAC inhibitors as chemical probes and therapeutic agents.

Reference

Journal : Nat. Chem. Biol.

Title : Chemical phylogenetics of histone deacetylases.

PubMed ID : 20139990

DOI : 10.1038/nchembio.313

Year : 2010

Volume : 6

Issue : 3

First Page : 238

Last Page : 243

Authors : Bradner JE, West N, Grachan ML, Greenberg EF, Haggarty SJ, Warnow T, Mazitschek R.

Reference

Journal : Nat. Chem. Biol.

Title : Chemical phylogenetics of histone deacetylases.

PubMed ID : 20139990

DOI : 10.1038/nchembio.313

Year : 2010

Volume : 6

Issue : 3

First Page : 238

Last Page : 243

Authors : Bradner JE, West N, Grachan ML, Greenberg EF, Haggarty SJ, Warnow T, Mazitschek R.

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
Concentration required to inhibit human Histone deacetylase (HDAC) enzyme by 50%	Homo sapiens	200.0 nM
Inhibition of human HDAC1	Homo sapiens	2.7 nM
Inhibition of human HDAC3	Homo sapiens	8.0 nM
Inhibition of human HDAC6	Homo sapiens	4.8 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	40.7 %
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate	Severe acute respiratory syndrome coronavirus 2	12.89 %
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	1.05 %	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	1.05 %

Related Entries

Generate Knowledge Graph

Chemical clusters of APIs

MCS-substructure mapping similar to an API

MCS-substructure mapping to Bioactive chemicals

Cross References

Resources	Reference
ChEBI	93953
ChEMBL	CHEMBL353581
DrugBank	DB12847
FDA SRS	12N86DSS23
PubChem	4996
SureChEMBL	SCHEMBL154681
ZINC	ZINC000003820709

CONTENTS

Structure
Chemical and Physical Properties
Related Entries