Synthesis and evaluation of α-aminoacyl amides as antitubercular agents effective on drug resistant tuberculosis

Vitthal B Makane; Vagolu Siva Krishna; E Vamshi Krishna; Manjulika Shukla; B Mahizhaveni; Sunil Misra; Sidharth Chopra; Dharmarajan Sriram; V N Azger Dusthackeer; Haridas B Rode

doi:10.1016/j.ejmech.2019.01.002

Synthesis and evaluation of α-aminoacyl amides as antitubercular agents effective on drug resistant tuberculosis

Eur J Med Chem. 2019 Feb 15:164:665-677. doi: 10.1016/j.ejmech.2019.01.002. Epub 2019 Jan 3.

Affiliations

¹ Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500 007, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201 002, India.
² Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, R.R. District, Hyderabad, 500 078, India.
³ Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201 002, India; Department of Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500 007, India.
⁴ Department of Microbiology, CSIR-Central Drug Research Institute, Lucknow, 226021, Uttar Pradesh, India.
⁵ Department of Bacteriology, National Institute for Research in Tuberculosis, Chennai, India.
⁶ Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500 007, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201 002, India. Electronic address: haridas.rode@iict.res.in.

PMID: 30654238
DOI: 10.1016/j.ejmech.2019.01.002

Abstract

The development of an effective antitubercular agent is a challenge due to the complex nature of tuberculosis. Herein, we report the synthesis and evaluation of α-aminoacyl amides as antitubercular agents. The systematic medicinal chemistry approach led to identification of optimal substitutions required for the activity. Compound 11l was identified as antitubercular lead with drug like properties. Further, 11l selectively inhibited M. tuberculosis H37Rv with MIC value of 0.78 μM and was found to be non-toxic to CHOK1 cells. The lead compound inhibited multidrug resistant and Pre-Extensively drug resistant strains of Mycobacterium at 2 μg/mL and 8 μg/mL respectively.

Keywords: Antitubercular agents; Drug-resistant tuberculosis; Heterocyclic compounds; Ugi reaction.

MeSH terms

Amides / chemistry
Amides / pharmacology*
Animals
Antitubercular Agents / chemistry*
Antitubercular Agents / pharmacology
Cell Line
Chemistry, Pharmaceutical / methods*
Humans
Microbial Sensitivity Tests
Mycobacterium tuberculosis / drug effects
Tuberculosis, Multidrug-Resistant / drug therapy*

Substances

Amides
Antitubercular Agents