Diseño y selección por topología molecular de nuevos compuestos antimicobacterianos

Abstract

Molecular topology, MT, has been used to select new active compounds against Mycobacterium tuberculosis (MTBC) and Mycobacterium avium complex (MAC). MT has proved to be a useful formalism to find quantitative structureactivity relations (QSAR), based on the numeric characterization of the molecules through topological indices (TI), that is to say, to obtain the topological functions: P(TI) = A0 + ?Ai(TIi), where P represents the property, A0 the intercept and Ai the regression coefficients. In order to the effectiveness of the functions, four new families of TI were introduced. Once calculated the TI of forty five active compounds, the predictive functions as well as the discriminant functions allowing us to discriminate among active and inactive compounds, were achieved. Next the molecular models were designed using the selected functions, and they were applied to databases of chemical structures for the selection of potentially active substances. Finally, we carried out the in vitro assays in order to check the minimal inhibitory concentration (MIC) of the selected compounds. Conclusions: 1. The new TI contribute to improve in more than 30% of the predictive functions on those already described, and also to a significant effectiveness to discriminate among active and inactive compounds against MTBC and MAC. 2. The obtained functions have demonstrated that it is possible to predict efficiently the MIC and other pharmacological properties of the active compounds. 3. Useful models have been obtained for the selection of active compounds against MTBC and MAC. 4. After in vitro tests at the laboratory, the following results stand out: 10 compounds were active against MTBC (MIC=16?g/mL): BAK, DNOC, DOCA, linezolid, paromomycin, pentamidine, reserpine, ribavirin, TPEN and trifluoperazine. 6 were active against MAC (MIC=16?g/mL): BAK, linezolid, paromomycin, TPEN, trifluoperazine and pentamidine. Six new substituted pirimidines synthesized at the University of Gerona were selected. Theoretically they present a good pharmacological profile and their in vitro assays demonstrated that the MIC against MTBC were between 32 and 64 ?g/mL, what induces us to consider these structures as new leads as antituberculosis agents.