Michael Adduct of Sulfonamide Chalcone Targets Folate Metabolism in Brugia Malayi Parasite

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...

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Published inBiomedicines Vol. 11; no. 3; p. 723
Main Authors Bhoj, Priyanka S, Bahekar, Sandeep P, Chowdhary, Shambhavi, Togre, Namdev S, Amdare, Nitin P, Jena, Lingaraj, Goswami, Kalyan, Chandak, Hemant
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 27.02.2023
MDPI
Subjects
Adducts
antifilarial
Apoptosis
Cytochrome c
Dihydrofolate reductase
Enzyme-linked immunosorbent assay
Epicatechin
Filariasis
Flavonoids
folate metabolism
Folic acid
Metabolism
Metabolites
Michael adducts
Parasites
Physiological aspects
sulfonamide chalcone
Sulfonamides
Vitamin B
India
United States > US
Michael adducts
sulfonamide chalcone
folate metabolism
dihydrofolate reductase
antifilarial
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Summary: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 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.
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These authors contributed equally to this work.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines11030723