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Enone- and chalcone-chloroquinoline hybrid analogues: in silico guided design, synthesis, antiplasmodial activity, in vitro metabolism, and mechanistic studies.

ABSTRACT: Analogues of the previously reported antimalarial hybrid compounds 8b and 12 were proposed with the aim of identifying compounds with improved solubility and retained antimalarial potency. In silico characterization predicted improved solubilities of the analogues, particularly at low pH; they retained acceptable predicted permeability properties but were predicted to be susceptible to hepatic metabolism. These analogues were synthesized and found to exhibit notable in vitro antimalarial activity. Compounds 25 and 27 were the most active of the analogues. In vitro metabolism studies indicated susceptibility of the analogues to hepatic metabolism. There was also evidence of primary glucuronidation for analogues 24-27. Presumed cis-trans isomerism of 12, 22, and 23 under in vitro metabolism assay conditions was also observed, with differences in the nature and rates of metabolism observed between isomers. Biochemical studies strongly suggested that inhibition of hemozoin formation is the primary mechanism of action of these analogues.

SUBMITTER: Guantai EM

PROVIDER: S-EPMC3104272 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Enone- and chalcone-chloroquinoline hybrid analogues: in silico guided design, synthesis, antiplasmodial activity, in vitro metabolism, and mechanistic studies.

Guantai Eric M EM Ncokazi Kanyile K Egan Timothy J TJ Gut Jiri J Rosenthal Philip J PJ Bhampidipati Ravi R Kopinathan Anitha A Smith Peter J PJ Chibale Kelly K

Journal of medicinal chemistry 20110505 10

Analogues of the previously reported antimalarial hybrid compounds 8b and 12 were proposed with the aim of identifying compounds with improved solubility and retained antimalarial potency. In silico characterization predicted improved solubilities of the analogues, particularly at low pH; they retained acceptable predicted permeability properties but were predicted to be susceptible to hepatic metabolism. These analogues were synthesized and found to exhibit notable in vitro antimalarial activit ...[more]

PMID: 21500839

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Project description:In tropical and subtropical areas, malaria stands as a profound public health challenge, causing an estimated 247 million cases worldwide annually. Given the absence of a viable vaccine, the timely and effective treatment of malaria remains a critical priority. However, the growing resistance of parasites to currently utilized drugs underscores the critical need for the identification of new antimalarial therapies. Here, we aimed to identify potential new drug candidates against Plasmodium falciparum, the main causative agent of malaria, by analyzing the transcriptomes of different life stages of the parasite and identifying highly expressed genes. We searched for genes that were expressed in all stages of the parasite's life cycle, including the asexual blood stage, gametocyte stage, liver stage, and sexual stages in the insect vector, using transcriptomics data from publicly available databases. From this analysis, we found 674 overlapping genes, including 409 essential ones. By searching through drug target databases, we discovered 70 potential drug targets and 75 associated bioactive compounds. We sought to expand this analysis to similar compounds to known drugs. So, we found a list of 1557 similar compounds, which we predicted as actives and inactives using previously developed machine learning models against five life stages of Plasmodium spp. From this analysis, two compounds were selected, and the reactions were experimentally evaluated. The compounds HSP-990 and silvestrol aglycone showed potent inhibitory activity at nanomolar concentrations against the P. falciparum 3D7 strain asexual blood stage. Moreover, silvestrol aglycone exhibited low cytotoxicity in mammalian cells, transmission-blocking potential, and inhibitory activity comparable to those of established antimalarials. These findings warrant further investigation of silvestrol aglycone as a potential dual-acting antimalarial and transmission-blocking candidate for malaria control.

Dataset Information

Enone- and chalcone-chloroquinoline hybrid analogues: in silico guided design, synthesis, antiplasmodial activity, in vitro metabolism, and mechanistic studies.

Publications

Enone- and chalcone-chloroquinoline hybrid analogues: in silico guided design, synthesis, antiplasmodial activity, in vitro metabolism, and mechanistic studies.

Similar Datasets

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