1. Michael Adduct of Sulfonamide Chalcone Targets Folate Metabolism in Brugia Malayi Parasite.
- Author
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Bhoj, Priyanka S., Bahekar, Sandeep P., Chowdhary, Shambhavi, Togre, Namdev S., Amdare, Nitin P., Jena, Lingaraj, Goswami, Kalyan, and Chandak, Hemant
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CHALCONE ,SULFONAMIDES ,FOLIC acid ,METABOLISM ,CYTOCHROME c ,SULFONAMIDE drugs ,CHALCONES - Abstract
A series of Michael adducts of malononitrile and sulfonamide chalcones were synthesized, characterized, and evaluated for their antifilarial activity. Out of 14 compounds, N-(4-(4,4-dicyano-3-p-tolylbutanoyl)phenyl)benzenesulfonamide showed favorable drug-likeness properties with marked antifilarial effects at micro-molar dosages. Apoptosis in Brugia malayi microfilariae was confirmed by EB/AO staining, MTT assay, and cytoplasmic cytochrome c ELISA. Since chalcone and folate synthesis pathways share the same substrate, we hypothesize a structural analogy-based inhibition of folate metabolism by this compound. Molecular docking against a pre-validated BmDHFR protein showed more favorable thermodynamic parameters than a positive control, epicatechin-3-gallate. The compound significantly suppressed the DHFR activity in a parasite extract in vitro. Our hypothesis is also supported by a significant reversal of DHFR inhibition by folate addition, which indicated a plausible mechanism of competitive inhibition. These results demonstrate that targeting filarial folate metabolism through DHFR with consequent apoptosis induction might be rewarding for therapeutic intervention. This study reveals a novel rationale of the structural analogy-based competitive inhibition of DHFR by Michael adducts of sulfonamide chalcones. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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