Clinical Needs as a Starting Point for Different Strategies in Computational Drug Development.

Traditionally, the first step in the development of drugs is the definition of the target, by choice of a biological structure involved in a disease or by recognition of a molecule with some degree of a biological activity that presents itself as druggable and endowed with therapeutic potential. The complexity of the pathophysiological mechanisms of disease and of the structures of the molecules involved creates several challenges in this drug discovery process. These difficulties also come from independent operation of the different parts involved in drug development, with little interaction between clinical practitioners, academic institutions and large pharmaceutical companies.

Synthesis and antimalarial properties of new chloro-9H-xanthones with an aminoalkyl side chain.

The synthesis and antimalarial properties of twelve new chlorinated 9H-xanthones, carrying a [2-(diethylamino)ethyl]amino group in position 1, are reported. All compounds were found to be active towards the chloroquine-susceptible and chloroquine-resistant strains 3D7 and Dd2, resp., of the protozoa parasite Plasmodium falciparum.

Psoralen analogues: synthesis, inhibitory activity of growth of human tumor cell lines and computational studies.

Eight psoralens have been evaluated for their ability to inhibit the in vitro growth of three human tumor cell lines representing different tumor types, MCF-7 (breast cancer), NCI-H460 (non-small cell lung cancer) and SF-268 (CNS cancer). The synthesis of four new psoralens (benzofurocoumarins) is presented as well as the results of the ab initio calculations to find the parameters that relate the structure with the antitumor activity. This work provides supplementary information that could allow the development of new psoralen analogues with this type of biological activity.

Definition of an electronic profile of compounds with inhibitory activity against hematin aggregation in malaria parasite.

Malaria is one of the most important parasitic diseases, affecting almost half of the world and posing a threat to the other half. Xanthone derivatives can behave as antimalarial drugs in the same mechanistic way as chloroquine and other related quinolines. This action is due to the inhibition of the detoxification pathway of the parasite, responsible for the production of hemozoin.

Computational studies of new potential antimalarial compounds--stereoelectronic complementarity with the receptor.

One of the most important pharmacological mechanisms of antimalarial action is the inhibition of the aggregation of hematin into hemozoin. We present a group of new potential antimalarial molecules for which we have performed a DFT study of their stereoelectronic properties. Additionally, the same calculations were carried out for the two putative drug receptors involved in the referred activity, i.

Receptor-drug association studies in the inhibition of the hematin aggregation process of malaria.

Docking studies were performed to investigate the binding of several antimalarial compounds to the putative drug receptors involved in the hematin aggregation process. These studies reveal a binding profile that correlates with the complementarity of electrostatic potentials between the receptors and the active molecules. These results allow a possible explanation for the same molecular mechanism shown by 4-aminoquinolines, quinine, mefloquine, halofantrine and hydroxylated xanthones.