Among infectious diseases, tuberculosis continues to be a major cause of death. The rise of virulent and drug-resistant forms of the causative organism, Mycobacterium tuberculosis (Mtb), may have the capacity to return therapy regimens to the pre-antibiotic age. This stark situation makes urgent the exploration of new space in drug discovery. In our laboratories, we have been investigating six-membered aliphatic heterocycles bearing sulfonyl or thioureido groups for their potential anti-tubercular activities (Scheme, compounds II). We now describe the ready preparation of such materials on gram scale and in shelf-stable form, along with a preliminary biological assessment. In a representative procedure, the addition of 2,4-dichlorobenzenesulfonyl chloride to I (X = N(CH3)) in ethyl acetate rapidly precipitated the corresponding sulfonyl hydrazide as the hydrochloride salt (II, X = N(CH3), Y = SO2R1HCl, R1 = 2,4-Cl2Ph, 89%): mp 193°C (dec); FT-IR: 3095, 2958, 2588, 1374, 1164; H-NMR (500 MHz, DMSO-d6): δ 11.08 (br s, 1H), 9.80 (br s, 1H), 8.02 (d), 7.88 (d), 7.66 (dd), 3.06-2.92 (m, 8H), 2.61 (s, 3H); C-NMR (125 MHz, DMSO-d6): δ 139.01, 135.63, 134.07, 132.67, 131.85, 128.29, 52.16, 52.06, 42.31. Calcd for C11H15Cl2N3O2S: C, 36.62; H, 4.47; N, 11.64. Found: C, 36.77; H, 4.27; N, 11.67. Preliminary disc diffusion assays and inhibitory concentration determinations of some II against Mtb justify further examination of their antitubercular properties.

Preparation and characterization of novel six-membered aliphatic heterocycles as potential antitubercular agents

ACS Spring Meeting 2021

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