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

• Published in: Bioorganic & medicinal chemistry 2022-06, Vol.64, p.116777-116777, Article 116777
• Main Authors: Kumar Sahoo, Santosh, Maddipatla, Sarvan, Nageswara Rao Gajula, Siva, Naiyaz Ahmad, Mohammad, Kaul, Grace, Nanduri, Srinivas, Sonti, Rajesh, Dasgupta, Arunava, Chopra, Sidharth, Madhavi Yaddanapudi, Venkata
• Format: Article
• Language: English
• Subjects: Benzoxazole-2-amine-chalcone hybrids; Metabolic stability; Nitrofuran; Smile rearrangement; Time kill kinetics; Tuberculosis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2022.116777

[Display omitted] •New benzoxazole-2-amine linked chalcone hybrids were developed.•Antimycobacterial and antibacterial screening indicated selectivity towards Mtb.•Cell viability test against Vero cells was performed to determine toxicity.•Activity against clinical isolates of drug-resistant Mtb strains was evaluated.•Time kill analysis identified the lead compound demonstrating bactericidal efficacy. 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.