Synthesis, characterization, antimicrobial, cytotoxic and carbonic anhydrase inhibition activities of multifunctional pyrazolo-1,2-benzothiazine acetamides.

Abstract

The advent of antibiotic resistance in microorganisms requires the discovery and synthesis of novel antibiotics. At the same time, human pathogens are contributing to chronic and persistent inflammation. Motivated by these two concerning issues, new antibiotic drug candidates are synthesized by incorporation of benzothiazine, pyrazole, and amide moieties in a new scaffold to create multifunctional derivatives of pyrazolo-1,2-benzothiazine. The presented compounds have been synthesized and analyzed using spectroscopic and spectrometric techniques including FTIR, HRMS, ¹H and ¹³C NMR spectroscopy. All compounds were tested against five human microbial strains including three different strains of Staphylococcus aureus (ATCC 25923, ATCC BAA-41, and ATCC BAA-44), Escherichia coli (ATCC 8739), and Candida albicans (ATCC 90027) to evaluate their antibiotic potential. The results showed that out of fourteen synthesized compounds, 7b (MIC₉₀ = 16 μg/mL) and 7h (MIC₉₀ = 8.0 μg/mL) exhibited potent antibiotic activity against different strains of S. aureus (susceptible, methicillin-resistant, and multidrug-resistant). Cytotoxic studies against the human colon cancer mammalian cell line HCT-116 (ATCC CCL-247) revealed that only compound 7l inhibited cell viability, while the rest of the compounds including 7b and 7h showed no significant decrease in mammalian cell viability. Results of human carbonic anhydrase (hCA) inhibition assays discovered that monoalkylated derivatives have low to negligible inhibition potential but dialkylated ones have no inhibition potential at all for directed CAs (I, II, IX, and XII). From the low inhibiting compounds, 7b showed the highest inhibition potential with a minimum K _i value of 72.9 μM. In light of the above findings, these newly prepared scaffolds are valuable additions to the class of pyrazolo-1,2-benzothiazine antibiotics with selective antistaphylococcal activity.