Dihydrobenzothiazole coupled N-piperazinyl acetamides as antimicrobial agents: Design, synthesis, biological evaluation and molecular docking studies.

Abstract

Substituted saturated N-heterocycles have gained momentum as effective scaffolds for the development of new drugs. In this study, we coupled partly saturated benzothiazoles with substituted piperazines and evaluated their antimicrobial activity. Following a three-step reaction sequence from commercially available cyclic 1,3-diones, a series of novel 2-[4-substituted-1-piperazinyl]-N-(7-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)acetamides (7a-af) were synthesised. 2-Amino-5,6-dihydro-benzo[d]thiazol-7(4H)-ones, obtained through the condensation of cyclohexane-1,3-diones with thiourea, were acetylated with chloroacetic chloride and then reacted with N-substituted piperazines 6a-p to give the desired products 7a-af in excellent yields. All 32 new compounds were fully characterised by their 1 H-nuclear magnetic resonance (NMR), 13 C-NMR and high-resolution mass spectrometry spectra. The synthetic compounds 7a-af were tested in vitro for their efficacy as antimicrobials against pathogenic strains of Gram-positive and Gram-negative bacteria, Streptococcus mutans and Salmonella typhi, respectively, as well as against fungal strains, including Candida albicans 3018 and C. albicans 4748. Ciprofloxacin and fluconazole served as the reference drugs. While compounds 7c and 7l showed inhibition against fungal strains with zones of inhibition of 11 and 1 mm, respectively, four analogues (7d, 7l, 7n, and 7r) demonstrated strong antibacterial action (zone of inhibition in the range of 10-15 mm). Three compounds (7j, 7l, and 7w) also exhibited moderate antitubercular activity (MIC: 6.25 µg/mL) against Mycobacterium tuberculosis H37Rv. Molecular docking investigations and the predicted physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties for the potent compounds made this scaffold useful as a pharmacologically active framework for the development of potential antimicrobial hits.