Although its incidence in western Europe and North America is currently low, tuberculosis remains pervasive in much of the rest of the world, infecting as much as one-third of the planet’s population. The development of alarmingly virulent and drug-resistant forms of Mycobacterium tuberculosis (Mtb) infection has the capacity to return therapy of this chronic disease to the pre-antibiotic age, the era of tuberculosis sanatoria and radical surgical interventions. This glaring circumstance demands further mapping of new territory in anti-tubercular drug discovery. In our laboratories, we have recently been investigating functionalized six-membered aliphatic heterocycles (Scheme) for their potential anti-tubercular activities. We now report on the ready preparation of new examples of such materials (Compounds II, X = N(CH3), R1,R2 = CH(CH=CH)mAr) on gram scale and in shelf-stable form and include the results of preliminary biological assays. In a representative procedure, the condensation of I (X = N(CH3)) with ortho-pyrocatechualdehyde in ethanol rapidly precipitated the corresponding 4-methyl-N-(2,3-dihydroxyphenylmethylene)-1-piperazinamine (II, X = N(CH3), R1,R2 = CH(CH=CH)mAr, m = 0, Ar = 2,3-(OH)2C6H3 (III), 84%): mp 197°C (dec); FT-IR (ATR, cm-1): 3200-2500 (br), 3007, 2975, 2858, 1567, 1354, 1228, 1203; H-NMR (500 MHz, DMSO-d6): δ 11.20 (brs), 9.03 (brs), 7.85 (s, 1H), 7.79 (dd, 1H), 6.71 (dd, 1H), 6.66 (t, 1H), 3.09 (m, 4H), 2.49 (m, ~4H, conflated with NMR solvent), 2.22 (s, 3H); C-NMR (125 MHz, DMSO-d6): δ 145.69, 145.56, 140.65, 120.20, 120.18, 119.23, 116.15, 54.08, 51.15, 45.90. Anal. Calcd for C12H17N3O2: C, 61.25; H, 7.28; N, 17.85. Found: C, 61.18; H, 7.22; N, 17.89. A Kirby-Bauer disc diffusion assay done with compound III against Mycobacterium bovis BCG (a surrogate for Mtb) yielded a large zone of inhibition. Subsequent microtiter broth dilution testing against Mtb strain Erdman demonstrated a minimum inhibitory concentration of 16 ug/mL. Similar results were observed for several other members of this compound class, justifying further examination of their anti-tubercular properties.

New 4-methyl-N-(arylmethylene)-1-piperazinamines and their activities against Mycobacterium tuberculosis

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