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Arch Pharm (Weinheim). 2019 Apr;352(4):e1800290. doi: 10.1002/ardp.201800290. Epub 2019 Feb 25.

Design and synthesis of imidazolidinone derivatives as potent anti-leishmanial agents by bioisosterism.

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Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, India.
Department of Bioscience and Biotechnology, Banasthali Vidyapeeth University, Vanasthali, India.
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Greater Noida, India.


Bioisosterism is a useful strategy in rational drug design to improve pharmacodynamic and pharmacokinetic properties of lead compounds. Imidazolidinones have been reported as potent kinase inhibitors and antileishmanial agents. In this study, bioisosteres of imidazolidinones (compounds 1-3) were evaluated for their antileishmanial properties. The modified imidazolidinones exhibited potent antileishmanial activity against extracellular as well as intracellular Leishmania donovani parasites in nanomolar concentrations. The selectivity index of these compounds on host cells was found to be more than 1000, emphasizing their specificity toward the parasite. Using SwissTargetPrediction software, we assessed the potential targets of these compounds and found MAPK as the most probable target. To in vitro validate, we developed a novel in vitro kinase assay that mimics the in vivo nature of the functional kinome. Compounds 1-3 displayed specific inhibition of parasite kinase activity accompanied by an increase in intracellular sodium levels in the parasites. This might be the effect of kinase inhibition that regulates sodium homeostasis through Na-ATPases. Finally, the compound-treated parasites underwent apoptosis-like death. This study represents bioisoterism as a novel approach for drug design to establish the structure-activity relationship, which in turn helps to improve the therapeutic activity of lead compounds.


bioisosterism; high-throughput kinase assay; imidazolidinones; leishmaniasis; target deconvolution

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