In this work the aim of study was the synthesis and evaluation of in vitro anti-Mycobacterium tuberculosis activity as well as the cytotoxicity in VERO cells of a series of 17 novel thiosemicarbazones derived from the natural monoterpene (-)-camphene by REMA and MTT methods. Overall, the majority of tested compounds exhibited considerable inhibitory effects on the growth of M. tuberculosis HRv, especially the derivatives 3, 4a-c, 4f, 4i, 4k, 5 and 6a-b. MIC values of 20 tested compounds ranged from 3.9 to > 250 μg/mL. It was found that when inserting new nitrogenous groups to the (-)-camphene increased the anti-M. tuberculosis activity of some compounds. The SI was calculated for all compounds that showed highly potent anti-M. tuberculosis activity and the best SI values were 21.36, 26.92 and 31.62 (4b, 6a and 6b), and may be considered potential candidates for future antituberculosis drugs.

Background: For more than 60 years, the lack of new anti-tuberculosis drugs and the increase of resistant Mycobacterium tuberculosis lineages exhibit a therapeutic challenge, demanding new options for the treatment of resistant tuberculosis. Objective: Herein, we determined the (i) activities of (-)-camphene and derivatives and (ii) combinatory effect with pyrazinamide (PZA) against Mycobacterium tuberculosis in acidic pH and (iii) cytotoxicity in VERO cells. Methods: The activity of (-)-camphene and 15 derivatives were determined in M. tuberculosis H37Rv in culture medium at pH 6.0 by Resazurin Microtiter Assay Plate (REMA). The combinatory study of three (-)-camphene derivatives with PZA was carried out in seven multidrug-resistant (MDR) clinical isolates by REMA and Checkerboard, respectively. The assay of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide in VERO cells was used to determine the derivatives cytotoxicity. Results: Four (-)-Camphene derivatives, (4), (5a) (5d) and (5h), showed reduction in MIC value at pH 6.0 compared to MIC detected at pH 6.8 in M. tuberculosis H37Rv and multidrug resistant clinical isolates. Three (-)-camphene derivatives, (4), (5d) and (5h), showed synergistic effect (FICI ≤ 0.5) combined with PZA and were more selective for M. tuberculosis than VERO cell (selective index from 7.7 to 84.2). Conclusion: Three (-)-camphene derivatives have shown to be promising anti-TB molecule scaffold due to the low MIC values in acidic pH against MDR M. tuberculosis clinical isolates, synergism with PZA and low cytotoxicity.

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