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Molecular modeling studies, synthesis and biological evaluation of derivatives of N-phenylbenzamide as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors

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Abstract

The search for new antimalarial agents is necessary as current drugs in the market have become vulnerable due to the emergence of resistant strains of Plasmodium falciparum (Pf). The enzyme dihydroorotate dehydrogenase (PfDHODH) is a validated target for development of antimalarial agents. PfDHODH is a crucial enzyme in the de novo pyrimidine biosynthesis pathway and is essential for the growth of the parasite. In this article, we report the design, synthesis and evaluation of benzanilides as inhibitors of PfDHODH. From the pool of molecules designed using molecular modeling techniques, candidates were shortlisted for further evaluation based on docking scores and 3D-QSAR studies. The activities of these shortlisted analogs were predicted from CoMFA and CoMSIA models. The most promising molecules were synthesized using solvent-free microwave-assisted synthesis and their structures characterized by spectroscopic techniques. The molecules were screened for in vitro antimalarial activity by the whole cell assay method. Two molecules viz. KMC-3 and KMC-15 were found to be active at 8.7 and 5.7 μM concentrations, respectively.

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Acknowledgements

K. R. Desai is grateful to the All India Council for Technical Education (AICTE), New Delhi for support as JRF. The Department of Science and Technology (DST), New Delhi is thanked for facilities provided to the department through their FIST program (SR/FST/LSI-163/2003). We also would like to thank Ian Bathurst, Director, Drug Discovery and Technology, Medicines for Malaria Venture, Geneva, Switzerland and Sergio Wittlin, Head, Malaria Drug Discovery Group, Swiss Tropical Institute, Socinstrasse, Basel, Switzerland for antimalarial evaluation.

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  1. Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, 400 098, India

    Kumar R. Desai, Mushtaque S. Shaikh & Evans C. Coutinho

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  1. Kumar R. Desai
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  2. Mushtaque S. Shaikh
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  3. Evans C. Coutinho
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Correspondence to Evans C. Coutinho.

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Desai, K.R., Shaikh, M.S. & Coutinho, E.C. Molecular modeling studies, synthesis and biological evaluation of derivatives of N-phenylbenzamide as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. Med Chem Res 20, 321–332 (2011). https://doi.org/10.1007/s00044-010-9323-4

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