Development of 2-(4-oxoquinazolin-3(4H)-yl)acetamide derivatives as novel enoyl-acyl carrier protein reductase (InhA) inhibitors for the treatment of tuberculosis

Ganesh S Pedgaonkar; Jonnalagadda Padma Sridevi; Variam Ullas Jeankumar; Shalini Saxena; Parthiban Brindha Devi; Janupally Renuka; Perumal Yogeeswari; Dharmarajan Sriram

doi:10.1016/j.ejmech.2014.09.028

Development of 2-(4-oxoquinazolin-3(4H)-yl)acetamide derivatives as novel enoyl-acyl carrier protein reductase (InhA) inhibitors for the treatment of tuberculosis

Eur J Med Chem. 2014 Oct 30:86:613-27. doi: 10.1016/j.ejmech.2014.09.028. Epub 2014 Sep 9.

Authors

Ganesh S Pedgaonkar¹, Jonnalagadda Padma Sridevi¹, Variam Ullas Jeankumar¹, Shalini Saxena¹, Parthiban Brindha Devi¹, Janupally Renuka¹, Perumal Yogeeswari¹, Dharmarajan Sriram²

Affiliations

¹ Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad, A.P. 500078, India.
² Department of Pharmacy, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad, A.P. 500078, India. Electronic address: drdsriram@yahoo.com.

PMID: 25218910
DOI: 10.1016/j.ejmech.2014.09.028

Abstract

InhA, the enoyl acyl carrier protein reductase of Mycobacterium tuberculosis (MTB) is an attractive target for developing novel anti-tubercular agents. Twenty eight 2-(4-oxoquinazolin-3(4H)-yl)acetamide derivatives were synthesized and evaluated for their in vitro MTB InhA inhibition. Compounds were further evaluated for their in vitro activity against drug sensitive and resistant MTB strains and cytotoxicity against RAW 264.7 cell line. Compounds were docked at the active site of InhA to understand their binding mode and differential scanning fluorimetry was performed to ascertain their protein interaction and stability.

Keywords: Cytotoxicity; Enoyl acyl carrier protein reductase; InhA; Tuberculosis.

Publication types

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

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry
Acetamides / pharmacology*
Animals
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / genetics
Bacterial Proteins / metabolism
Cell Line
Cell Survival / drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Mice
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / enzymology
Oxidoreductases / antagonists & inhibitors*
Oxidoreductases / genetics
Oxidoreductases / metabolism
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology*
Structure-Activity Relationship
Tuberculosis / drug therapy*

Substances

2-(4-oxoquinazolin-3(4H)-yl)acetamide
Acetamides
Bacterial Proteins
Enzyme Inhibitors
Quinazolines
Oxidoreductases
InhA protein, Mycobacterium