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

Priyanka S. Bhoj; Sandeep P. Bahekar; Shambhavi Chowdhary; Namdev S. Togre; Nitin P. Amdare; Lingaraj Jena; Kalyan Goswami; Hemant Chandak

doi:10.3390/biomedicines11030723

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

Priyanka S. Bhoj, Sandeep P. Bahekar, Shambhavi Chowdhary, Namdev S. Togre, Nitin P. Amdare, Lingaraj Jena, Kalyan Goswami, Hemant Chandak

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	723
Journal	Biomedicines
Volume	11
Issue number	3
DOIs	https://doi.org/10.3390/biomedicines11030723
State	Published - Mar 2023
Externally published	Yes

Keywords

Michael adducts
antifilarial
dihydrofolate reductase
folate metabolism
sulfonamide chalcone

ASJC Scopus subject areas

Medicine (miscellaneous)
General Biochemistry, Genetics and Molecular Biology

Access to Document

10.3390/biomedicines11030723

Cite this

@article{2ddf0319bb3148528269ee4e74a63b36,

title = "Michael Adduct of Sulfonamide Chalcone Targets Folate Metabolism in Brugia Malayi Parasite",

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.",

keywords = "Michael adducts, antifilarial, dihydrofolate reductase, folate metabolism, sulfonamide chalcone",

author = "Bhoj, {Priyanka S.} and Bahekar, {Sandeep P.} and Shambhavi Chowdhary and Togre, {Namdev S.} and Amdare, {Nitin P.} and Lingaraj Jena and Kalyan Goswami and Hemant Chandak",

note = "Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = mar,

doi = "10.3390/biomedicines11030723",

language = "English (US)",

volume = "11",

journal = "Biomedicines",

issn = "2227-9059",

publisher = "MDPI AG",

number = "3",

}

TY - JOUR

T1 - Michael Adduct of Sulfonamide Chalcone Targets Folate Metabolism in Brugia Malayi Parasite

AU - Bhoj, Priyanka S.

AU - Bahekar, Sandeep P.

AU - Chowdhary, Shambhavi

AU - Togre, Namdev S.

AU - Amdare, Nitin P.

AU - Jena, Lingaraj

AU - Goswami, Kalyan

AU - Chandak, Hemant

PY - 2023/3

Y1 - 2023/3

N2 - 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.

AB - 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.

KW - Michael adducts

KW - antifilarial

KW - dihydrofolate reductase

KW - folate metabolism

KW - sulfonamide chalcone

UR - http://www.scopus.com/inward/record.url?scp=85152035385&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85152035385&partnerID=8YFLogxK

U2 - 10.3390/biomedicines11030723

DO - 10.3390/biomedicines11030723

M3 - Article

AN - SCOPUS:85152035385

SN - 2227-9059

VL - 11

JO - Biomedicines

JF - Biomedicines

IS - 3

M1 - 723

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this