Analysis of stereoelectronic properties, mechanism of action and pharmacophore of synthetic indolo[2,1-b]quinazoline-6,12-dione derivatives in relation to antileishmanial activity using quantum chemical, cyclic voltammetry and 3-D-QSAR CATALYST procedures.

Several indolo[2,1-b]quinazoline-6,12-dione (tryptanthrin) derivatives exhibited remarkable activity at concentrations below 100 ng/mL when tested against in vitro Leishmania donovani amastigotes. The in vitro toxicity studies indicate that the compounds are fairly well tolerated in both macrophage and neuronal lines. An analysis based on qualitative and quantitative structure-activity relationship studies between in vitro antileishmanial activity and molecular electronic structure of 27 analogues of indolo[2,1-b]quinazoline-6,12-dione is presented here by using a combination of semi-empirical AM1 quantum chemical, cyclic voltammetry and a pharmacophore generation (CATALYST) methods.

Antileishmanial activities of several classes of aromatic dications.

Aromatic dicationic molecules possess impressive activity against a broad spectrum of microbial pathogens, including Pneumocystis carinii, Cryptosporidium parvum, and Candida albicans. In this work, 58 aromatic cations were examined for inhibitory activity against axenic amastigote-like Leishmania donovani parasites. In general, the most potent of the compounds were substituted diphenyl furan and thiophene dications.

Angiogenesis inhibitors specific for methionine aminopeptidase 2 as drugs for malaria and leishmaniasis.

Methionine aminopeptidase 2 (MetAP2) is responsible for the hydrolysis of the initiator methionine molecule from the majority of newly synthesized proteins. We have cloned the MetAP2 gene from the malaria parasite Plasmodium falciparum (PfMetAP2; GenBank accession number AF348320). The cloned PfMetAP2 has no intron, consists of 1,544 bp and encodes a protein of 354 amino acids with a molecular mass of 40,537 D and an overall base composition of 72.