Design and activity of novel antimycobacterial compounds

AGUSTINA I. DE LA IGLESIA; ANDREA P. CAMINOS; JUAN M. BELARDINELLI; HÉCTOR R. MORBIDONI; GUILLERMO R. LABADIE

Sede de Gobierno de la Universidad Nacional de Rosario, Maipú 1065, Rosario, Argentina

Congreso; V CONGRESO ARGENTINO DE MICROBIOLOGÍA GENERAL; 2008

Sociedad Argentina de Microbiología General

With a death toll of more than two million deaths per year worldwide, Mycobacterium tuberculosis, the causative agent of human tuberculosis, is the deadliest bacterial pathogen. In spite of the efforts to eradicate this illness, the number of cases is rising. Two of the factors that are responsible for this increase are the few drugs available for an efficient treatment and the appearance and dissemination of multi-drug resistant strains. There is an on-going effort to develop new drugs by either identifying new targets or improving the efficiency of drugs currently in use. Two examples of the latter are ethambutol, an anti-tubercular drug of clinical use, and econazole, an anti-fungal compound with recently described anti-tubercular activity. In both cases, the targets have not been conclusively demonstrated although both are being used as scaffolds for the design of novel compounds with improved and more specific activity. Here we report the synthesis and anti-tubercular activity of two series of compounds, one of them -1, 2, 3 triazoles- made by “click chemistry”, and the second one by N-modification of alkyl diamines. Thirty-eight triazole compounds were tested against different strains of opportunistic (M. avium) and pathogenic (M. tuberculosis) mycobacteria. Two of the synthesized molecules (A4Z3 and A7Z1) showed activities at lower µg/mL concentration for M. avium with one of them (A7Z1) displaying high activity on M. tuberculosis; being more active that known anti-fungal azoles (econazole and clotrimazole) used as control drugs. Thirty-four diamines were also assayed for their anti- mycobacterial activity on M. avium and M. tuberculosis, with very promising results since six of these molecules exhibited strong activity (Minimum Inhibitory Concentration, MIC, ranging from 0.8 µg/mL to 6.25 µg/mL) against both species. Moreover, two other molecules exhibited good activity specifically against M. avium (MIC≤6.25 µg/mL). While 1, 2, 3 triazoles are also active against a panel of multi- drug resistant (MDR) M. tuberculosis strains, diamines are in the process of being evaluated. None of the molecules of both groups showed any citotoxicity when assayed on Vero cells, suggesting that a therapeutic use is possible. In summary, the molecules reported here are worth considering as scaffold for further improvement in their activity as well as in animal trials