SYNTHESIS AND IN VITRO ANTIMYCOBACTERIAL INVESTIGATION OF 2-/3-ALKOXYPHENYLCARBAMIC ACID DERIVATIVES CONTAINING 4′-(PYRIMIDIN-2′-YL)PIPERAZIN-1′-YL MOIETY

In present paper, a series of 2-/3-alkoxyphenylcarbamic acid derivatives 5a-5d containing 4 '-(pyrimidin-2 '-yl)piperazin-1 '-y1 fragment were synthesized and isolated as salts with hydrochloric acid. Chemical structures of prepared intermediates and final compounds were confirmed by IR, 1H NMR, and C-13 NMR spectral data. In addition, target molecules 5a-5d were characterized by MS as well as elemental analyses readouts. Prepared basic carbamates 5aB-5dB were investigated to consider some of their drug-like parameters known as Lipinski Rule of Five, i.e. molecular weight (<500), predicted values of log P for octan-1-ol/water system by applying Moriguchi prediction method (<= 4.15) or by using Leo's prediction approach (<= 5), number of hydrogen bond donors (5), number of hydrogen bond acceptors (<= 10), number of rotable bonds (<= 10) and, finally, the values of topological polar surface area (<= 140 angstrom(2)). Given compounds have entirely met the criteria formulated above. Assuming their delivery by oral route and absorption by passive mechanisms, evaluated molecules would be able to show good oral bioavailability. The salts 5a-5d were in vitro screened for the activity against virulent Mycobacterium tuberculosis CNCTC My. 331/88 (identical with H37Rv and ATCC 2794) and some of potentially pathogenic strains, i.e. M. avium CNCTC My. 330/80 (identical with ATCC 25291), M. kansasii CNCTC My. 235/80 (identical with ATCC 12478) and clinical isolate of M. kansasii 6509/96, respectively, by the dilution-micromethod using isoniazide and ethambutol as standard drugs. Following estimated values of minimum inhibitory concentration, current research suggested that the presence of 3-alkoxy side chain attached to phenylcarbamoyloxy fragment as well as relatively 7r-electron rich aromatic system(s) within basic compartment would be favorable in terms of the activity against M. tuberculosis H37Rv.