Synthesis and Biological Evaluation of Novel Benzhydrylpiperazine-Coupled Nitrobenzenesulfonamide Hybrids

Abstract

A series of novel benzhydryl piperazine-coupled nitrobenzenesulfonamide hybrids were synthesized with good to excellent yields. They were tested for in vitro inhibition of mycobacterial activity against the Mycobacterium tuberculosis H37Rv strain, in vitro cytotoxicity MTT (RAW 264.7cells) assay, nutrient starvation (H37Rv strain), and ability to block Cav3.2 T-type calcium channels. Novel hybrids did not inhibit T-type calcium channels, whereas they showed excellent antituberculosis (TB) activity and low cytotoxicity with a selectivity index of >30. A direct impact of the amino acid linker was not observed. Studied hybrids exhibited good inhibition activities, and the 2,4-dinitrobenzenesulfonamide group emerged as a promising scaffold for further drug design by hybridization approaches for anti-TB therapy.

Synthesis and biological evaluation of isatin oxime ether-tethered aryl 1H-1,2,3-triazoles as inhibitors ofMycobacterium tuberculosis

“…34 The cytotoxicity profile of anti -TB drugs isoniazid and rifampicin was also screened for comparison purpose (Table 1). 35 The SI values for 5d , 5e , and 5h are >30, indicating low cytotoxicity with high selectivity and additional suitability in order to generate potential lead antitubercular agents for further development.…”

Comprehensive Coverage on Anti‐mycobacterial Endeavour Reported in 2021

“…Vijayakumar et al have designed the novel benzhydryl piperazine-coupled nitrobenzenesulfonamide hybrids (11)(12)(13)(14)(15)(16)(17)(18) via molecular hybridization of benzhydrylpiperazine, amino acids, and nitrobenzenesulfonamide and revealed total eight derivatives with MICs of 0.78 μg/mL (Figure 6). [42] The MICs of these compounds were compared with isoniazid (0.05 μg/mL), ethambutol (1.56 μg/mL) and comparable with rifampicin (0.10 μg/mL). Further, 2,4-dinitro groups on benzene ring found to increase anti-TB activity rather than 2-or 4-nitro substitutions.…”

Design and characterisation of piperazine-benzofuran integrated dinitrobenzenesulfonamide as Mycobacterium tuberculosis H37Rv strain inhibitors

“…Indeed, sulphonamide analogues are known to exhibit a wide range of pharmacological activities particularly responsible for the enhanced anti-TB activity 12 , 13 . Moreover, our recent finding reveals that dinitro-substituted benzene derivatives have superior in vitro anti-TB activity 6 compared with monosubstituted benzene derivatives probably due to electron-deficient aromaticity 14 .…”

“…Benzofuran is a class of fused heterocyclic compound having oxygen with a large spectrum of biological activities 3 , 4 with relatively few examples of anti TB activity. The literature survey showed that piperazine incorporated benzofurans are important class of compounds, wherein piperazine expected to enhance selectivity and biological activity particularly in case of anti-TB activity 5 , 6 . 2-Substituted benzofurans exhibit promising anti-TB activity 7 .…”

“…The combination of pharmacophoric moieties of different bioactive compounds to produce a new hybrid with improved affinity, efficacy is a well-known concept in drug design and development 15 . Based on our prior efforts for the development of novel anti-TB agents, the aim of this study was to design new hybrid derivatives with increased activity against Mycobacterium tuberculosis ( Mtb ) 6 . Single hybrid architecture was successfully designed by linking four bioactive components such as substituted piperazine, 2-benzofuran, amino acids, and 2,4-dinitro-benzenesulfonamide.…”