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  3. Identification of nitrofuranylchalcone tethered benzoxazole-2-amines as potent inhibitors of drug resistant Mycobacterium tuberculosis demonstrating bactericidal efficacy

Identification of nitrofuranylchalcone tethered benzoxazole-2-amines as potent inhibitors of drug resistant Mycobacterium tuberculosis demonstrating bactericidal efficacy

  • Bioorg Med Chem. 2022 Jun 15;64:116777. doi: 10.1016/j.bmc.2022.116777.
Santosh Kumar Sahoo 1,  Sarvan Maddipatla 1,  Siva Nageswara Rao Gajula 2,  Mohammad Naiyaz Ahmad 3,  Grace Kaul 3,  Srinivas Nanduri 1,  Rajesh Sonti 4,  Arunava Dasgupta 5,  Sidharth Chopra 6,  Venkata Madhavi Yaddanapudi 7
Affiliations

Affiliations

  • 1 Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, Telangana, India.
  • 2 Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER),Balanagar, Hyderabad 500037, Telangana, India.
  • 3 Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Sector 10, Janakipuram Extension, Sitapur Road, Lucknow 226031, UP, India; AcSIR: Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
  • 4 Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER),Balanagar, Hyderabad 500037, Telangana, India. Electronic address: rajesh.sonti@niperhyd.ac.in.
  • 5 Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Sector 10, Janakipuram Extension, Sitapur Road, Lucknow 226031, UP, India; AcSIR: Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address: a.dasgupta@cdri.res.in.
  • 6 Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Sector 10, Janakipuram Extension, Sitapur Road, Lucknow 226031, UP, India; AcSIR: Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address: skchopra007@gmail.com.
  • 7 Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, Telangana, India. Electronic address: yssmadhavi@gmail.com.
PMID: 35487101 DOI: 10.1016/j.bmc.2022.116777
Abstract

Ever increasing drug resistance has become an impeding threat that continues to hamper effective tackling of otherwise treatable tuberculosis (TB). Such dismal situation necessitates identification and exploration of multitarget acting newer chemotypes with bactericidal efficacy as a priority, that could efficiently hinder uncontrolled spread of TB. In this context, herein we present design, synthesis and bio-evaluation of chalcone tethered bezoxazole-2-amines as promising anti-TB chemotypes. Preliminary screening of 24 compounds revealed initial hits 3,4,5-trimethoxyphenyl and 5-nitrofuran-2-yl derivative exhibiting selective inhibition of Mycobacterium tuberculosis (Mtb) H37Rv. Further, structural optimization of hit compounds generated 12 analogues, amongst which 5-nitrofuran-2-yl derivatives displayed potent inhibition of not only drug-susceptible (DS) Mtb but also clinical isolates of drug-resistant (DR) Mtb strains equipotently. Moreover, cell viability test against Vero cells found these compounds with favourable selectivity. Time kill analysis led to the identification of the lead compound (E)-1-(4-((5-chlorobenzo[d]oxazol-2-yl)amino)phenyl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one, that demonstrated bactericidal killing of Mtb bacilli. Together with acceptable microsomal stability, the lead compound of the series manifested all desirable traits of a promising antitubercular agent.

Keywords

Benzoxazole-2-amine-chalcone hybrids; Metabolic stability; Nitrofuran; Smile rearrangement; Time kill kinetics; Tuberculosis.

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