Synthesis and biological evaluation of 2-(Tetrazol-5-yl)sulfonylacetamides as inhibitors of Mycobacterium tuberculosis and Mycobacterium marinum

Abstract

A series of 2-(tetrazol-5-yl)sulfonylacetamide derivatives were synthesized and evaluated for their in vitro inhibitory activity against Mycobacterium tuberculosis (Mtb) and Mycobacterium marinum (Mm). The most active compounds exhibited in vitro MIC₉₀ values of 1.25 μg/mL against Mtb, but they were less effective against Mm (MIC₉₀ ≥ 10 μg/mL). Despite the most active compounds having favourable physicochemical properties and one of them having a half-life of ∼3 h when incubated with mouse liver microsomes, two representative highly active compounds showed strong chemical reactivity to cysteine derivatives, as surrogate in vivo sulfur-centred nucleophiles, indicating excessive electrophilicity, and therefore, likely indiscriminate chemical reactivity in vivo, representing an unacceptably high risk of general toxicity, and low likelihood of being therapeutically effective.

Keywords: 2-(Tetrazol-5-yl)sulfonylacetamide; Antimycobacterial activity; Cysteine; Electrophilicity; Mycobacterium tuberculosis; Pharmacokinetic; SAR; Synthesis.