Synthesis and biological evaluation of 2,4,5-trisubstituted thiazoles as antituberculosis agents effective against drug-resistant tuberculosis

Uttam B Karale; Vagolu Siva Krishna; E Vamshi Krishna; Amit S Choudhari; Manjulika Shukla; Vikas R Gaikwad; B Mahizhaveni; Sidharth Chopra; Sunil Misra; Dhiman Sarkar; Dharmarajan Sriram; V N Azger Dusthackeer; Haridas B Rode

doi:10.1016/j.ejmech.2019.05.082

Synthesis and biological evaluation of 2,4,5-trisubstituted thiazoles as antituberculosis agents effective against drug-resistant tuberculosis

Eur J Med Chem. 2019 Sep 15:178:315-328. doi: 10.1016/j.ejmech.2019.05.082. Epub 2019 Jun 4.

Authors

Affiliations

¹ Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India; Academy of Scientific and Innovative Research (AcSIR), 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 500078, India.
³ Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201 002, India; Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India.
⁴ Department of Biology, CSIR-National Chemical Laboratory, Pashan Road, Pune, 411008, India.
⁵ Department of Microbiology, CSIR-Central Drug Research Institute, Lucknow, 226021, Uttar Pradesh, India.
⁶ Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad, 500 037, India.
⁷ Department of Bacteriology, National Institute for Research in Tuberculosis, Chennai, 600031, India.
⁸ Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201 002, India; Department of Microbiology, CSIR-Central Drug Research Institute, Lucknow, 226021, Uttar Pradesh, India.
⁹ Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, 201 002, India. Electronic address: haridas.rode@iict.res.in.

PMID: 31195172
DOI: 10.1016/j.ejmech.2019.05.082

Abstract

The dormant and resistant form of Mycobacterium tuberculosis presents a challenge in developing new anti-tubercular drugs. Herein, we report the synthesis and evaluation of trisubstituted thiazoles as antituberculosis agents. The SAR study has identified a requirement of hydrophobic substituent at C2, ester functionality at C4, and various groups with hydrogen bond acceptor character at C5 of thiazole scaffold. This has led to the identification of 13h and 13p as lead compounds. These compounds inhibited the dormant Mycobacterium tuberculosis H37Ra strain and M. tuberculosis H37Rv selectively. Importantly, 13h and 13p were non-toxic to CHO cells. The 13p showed activity against multidrug-resistant tuberculosis isolates.

Keywords: Antituberculosis agents; Dormant tuberculosis; Drug resistant tuberculosis; Thiazoles; Tuberculosis.

MeSH terms

Antitubercular Agents / chemical synthesis
Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology*
Dose-Response Relationship, Drug
Humans
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*
Tuberculosis, Multidrug-Resistant / drug therapy*

Substances

Antitubercular Agents
Thiazoles