Development of novel tetrahydrothieno[2,3-c]pyridine-3-carboxamide based Mycobacterium tuberculosis pantothenate synthetase inhibitors: molecular hybridization from known antimycobacterial leads

Ganesh Samala; Parthiban Brindha Devi; Radhika Nallangi; Jonnalagadda Padma Sridevi; Shalini Saxena; Perumal Yogeeswari; Dharmarajan Sriram

doi:10.1016/j.bmc.2014.01.030

Development of novel tetrahydrothieno[2,3-c]pyridine-3-carboxamide based Mycobacterium tuberculosis pantothenate synthetase inhibitors: molecular hybridization from known antimycobacterial leads

Bioorg Med Chem. 2014 Mar 15;22(6):1938-47. doi: 10.1016/j.bmc.2014.01.030. Epub 2014 Feb 6.

Authors

Ganesh Samala¹, Parthiban Brindha Devi¹, Radhika Nallangi¹, Jonnalagadda Padma Sridevi¹, Shalini Saxena¹, Perumal Yogeeswari¹, Dharmarajan Sriram²

Affiliations

¹ Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
² Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.

PMID: 24565972
DOI: 10.1016/j.bmc.2014.01.030

Abstract

Twenty six 2,6-disubstituted 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide derivatives were designed by molecular hybridization approach using and synthesized from piperidin-4-one by five step synthesis. Compounds were evaluated for Mycobacterium tuberculosis (MTB) pantothenate synthetase (PS) inhibition study, in vitro activities against MTB, cytotoxicity against RAW 264.7 cell line. Among the compounds, 6-(4-nitrophenylsulfonyl)-2-(5-nitrothiophene-2-carboxamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (11) was found to be the most active compound with IC50 of 5.87 ± 0.12 μM against MTB PS, inhibited MTB with MIC of 9.28 μM and it was non-cytotoxic at 50 μM. The binding affinity of the most potent inhibitor 11 was further confirmed biophysically through differential scanning fluorimetry.

Keywords: Cytotoxicity; Pantothenate synthetase; Tuberculosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antitubercular Agents / chemical synthesis
Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / enzymology*
Peptide Synthases / antagonists & inhibitors*
Peptide Synthases / metabolism
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Thiophenes / chemical synthesis
Thiophenes / chemistry
Thiophenes / pharmacology*

Substances

6-(4-nitrophenylsulfonyl)-2-(5-nitrothiophene-2-carboxamido)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine-3-carboxamide
Antitubercular Agents
Enzyme Inhibitors
Sulfonamides
Thiophenes
Peptide Synthases
pantothenate synthetase