CONICET | Buscador de Institutos y Recursos Humanos

With a death toll of more than two million deaths per yearworldwide, Mycobacterium tuberculosis, the causative agent ofhuman tuberculosis, is the deadliest bacterial pathogen. Inspite of the efforts to eradicate this illness, the number of casesis rising. Two of the factors that are responsible for thisincrease are the few drugs available for an efficient treatmentand the appearance and dissemination of multi-drug resistantstrains. There is an on-going effort to develop new drugs byeither identifying new targets or improving the efficiency ofdrugs currently in use. Two examples of the latter areethambutol, an anti-tubercular drug of clinical use, andeconazole, an anti-fungal compound with recently describedanti-tubercular activity. In both cases, the targets have notbeen conclusively demonstrated although both are being usedas scaffolds for the design of novel compounds with improvedand more specific activity. Here we report the synthesis andanti-tubercular activity of two series of compounds, one ofthem -1, 2, 3 triazoles- made by click chemistry, and thesecond one by N-modification of alkyl diamines.Thirty-eight triazole compounds were tested against differentstrains of opportunistic (M. avium) and pathogenic (M.tuberculosis) mycobacteria. Two of the synthesized molecules(A4Z3 and A7Z1) showed activities at lower mg/mLconcentration for M. avium with one of them (A7Z1) displayinghigh activity on M. tuberculosis; being more active that knownanti-fungal azoles (econazole and clotrimazole) used as controldrugs.Thirty-four diamines were also assayed for their antimycobacterialactivity on M. avium and M. tuberculosis, withvery promising results since six of these molecules exhibitedstrong activity (Minimum Inhibitory Concentration, MIC,ranging from 0.8 mg/mL to 6.25 mg/mL) against both species.Moreover, two other molecules exhibited good activityspecifically against M. avium (MIC£6.25 mg/mL).While 1, 2, 3 triazoles are also active against a panel of multidrugresistant (MDR) M. tuberculosis strains, diamines are inthe process of being evaluated. None of the molecules of bothgroups showed any citotoxicity when assayed on Vero cells,suggesting that a therapeutic use is possible.In summary, the molecules reported here are worthconsidering as scaffold for further improvement in their activityas well as in animal trials.