International Journal of Drug Discovery

78-87

Authors: FARZAD KOBARFARD, SHOHREH MOHEBBI, FARSHAD H. SHIRAZI, SEYED HESAMEDIN SHARIFNIA

A drug-like molecule could be considered as a congregation of small fragments which are chemically linked to each other and the biological effect of such molecule is due to the contribution of these small fragments working together. This molecular unit has been constructed gradually through a multi-step synthesis route. Assessment of the biological activity of all the intermediary compounds of a multi-step synthesis process helps to track down the emergence of biological activity alongside the synthesis process and the results provide valuable clues about the SAR of the compounds. Furthermore unanticipated findings may be encountered if such approach is exercised. A two-step synthesis route was employed to make a few 2-aminopyrimidines from their corresponding enamine precursors. Both aminopyrimidines and enamines were subjected to antiproliferative and antimicrobial tests. Hit compounds with acceptable activities were found in both aminopyrimidine and enamine series. With respect to antimicrobial activity, enamine series were found more promising. This experiment sets an example for the applicability of our new approach called "Synthesis route-based hit identification" as a tool in medicinal chemistry to increase the hit rate in drug discovery processes.

100-117

Authors: LUIZ FREDERICO MOTTA, WANDA PEREIRA ALMEIDA

Candidiasis is recognized worldwide as an opportunistic infection. The severities of the infection increase in immunosuppression conditions with possible occurrence of visceral mycoses and sometimes are widespread and systemic. Increased resistance in strains of Candida albicans is a major obstacle to antifungal therapy. The aim of this study was to correlate the chemical structure of compounds with experimental data from biological activity anti-Candida albicans. We performed classical QSAR for a series of twenty derivatives of ketone -β unsaturated against resistant strains of Candida albicans. Ninety-four descriptors were calculated and multiparameter model was obtained through Partial Least Squares (PLS) method. The results showed that thermodynamic, dimensional and steric parameters are important in elucidating of action mechanism compounds. Four descriptors (molar refractivity, ionization potential, molecular length and Verloop B4) were selected and good model (n= 20; R2 = 0.776; SEC = 0.229; F(3,16) = 14.172; Q2LOO = 0.609; SEV = 0.295; Q2pred = 0.709; SEP = 0.091; k = 0.709; k’ = 1.00; ׀R20 – R’20׀ = 0.0009) was built with three latent variables describing 96.14% of the original information. Leave-N-out cross validation and Y-randomization analysis were performed in order to confirm the robustness of the model. The proposed model may provide a better understanding of the anti-Candida albicans activity of chalcones and can be used as guidance for proposition of new chemopreventive agents.