[show abstract][hide abstract] ABSTRACT: To streamline the preclinical phase of pharmaceutical development, we have explored the utility of structural data on the molecular target and synergy between computational and medicinal chemistry. We have concentrated on parasitic infectious diseases with a particular emphasis on the development of specific noncovalent inhibitors of proteases that play a key role in the parasites' life cycles. Frequently, the structure of the enzyme target of pharmaceutical interest is not available. In this setting we have modeled the structure of the relevant enzyme by virtue of its sequence similarity with proteins of known structure. For example, we have constructed a homology-based model of falcipain, the trophozoite cysteine protease, and used the computational ligand identification algorithm DOCK to identify in compuo enzyme inhibitors including oxalic bis(2-hydroxy-1-naphthyl-methylene)hydrazide (1) [Ring, C. S.; Sun, E.; McKerow, J. H.; Lee, G.; Rosenthal, P. J., Kuntz, I. D.; Cohen, F. E., Proc. Natl Acad. Sci. U.S.A. 1993, 90, 3583]. Compound 1 inhibits falcipain (IC50 6 microM) and the organism in vitro as judged by hypoxanthine uptake (IC50 7 microM). Following this lead, to date, we have identified potent bis arylacylhydrazides (IC50 150 nM) and chalcones (IC50 200 nM) that are active against both chloroquine-sensitive and chloroquine-resistant strains of malaria. In a second example, cruzain, the crystallographically determined structure of a papain-like cysteine protease, resolved to 2.35 A, was available. Aided by DOCK, we have identified a family of bis-arylacylhydrazides that are potent inhibitors of cruzain (IC50 600 microM). These compounds represent useful leads for pharmaceutical development over strict enzyme inhibition criteria in a structure-based design program.
[show abstract][hide abstract] ABSTRACT: A series of chalcones and their derivatives have been synthesized and identified as novel potential antimalarials using both molecular modeling and in vitro testing against the intact parasite. A large number of chalcones and their derivatives were prepared using one-step Claisen-Schmidt condensations of aldehydes with methyl ketones. These condensates were screened in vitro against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and shown to be active at concentrations in the nanomolar range. The most active chalcone derivative, 1-(2,5-dichlorophenyl)-3-(4-quinolinyl)-2-propen-1-one (7), had an IC50 value of 200 nM against both a chloroquine-resistant strain (W2) and a chloroquine-sensitive strain (D6). The resistance indexes for all compounds were substantially lower than for chloroquine, suggesting that this series will be active against chloroquine-resistant malaria. Structure-activity relationships (SAR) of the chalcones in the context of a homology-based model structure of the malaria trophozoite cysteine protease, the most likely target enzyme, are presented.
Journal of Medicinal Chemistry 01/1996; 38(26):5031-7. · 5.61 Impact Factor