Bhoj Priyanka S, Bahekar Sandeep P, Chowdhary Shambhavi, Togre Namdev S, Amdare Nitin P, Jena Lingaraj, Goswami Kalyan, Chandak Hemant
Department of Biochemistry, Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha 411002, India.
Department of Chemistry, G. S. Science, Arts and Commerce College, Sant Gadge Baba Amravati University, Khamgaon 444303, India.
Biomedicines. 2023 Feb 27;11(3):723. doi: 10.3390/biomedicines11030723.
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.
合成了一系列丙二腈与磺酰胺查尔酮的迈克尔加成物，对其进行了表征，并评估了它们的抗丝虫活性。在14种化合物中，N-(4-(4,4-二氰基-3-对甲苯基丁酰基)phenyl)苯磺酰胺显示出良好的类药性质，在微摩尔剂量下具有显著的抗丝虫作用。通过EB/AO染色、MTT法和细胞质细胞色素c ELISA法证实了微丝蚴的凋亡。由于查尔酮和叶酸合成途径共享相同的底物，我们推测该化合物基于结构类似物对叶酸代谢的抑制作用。与预先验证的BmDHFR蛋白进行分子对接显示，其热力学参数比阳性对照表儿茶素-3-没食子酸更有利。该化合物在体外显著抑制寄生虫提取物中的DHFR活性。叶酸添加导致DHFR抑制作用的显著逆转也支持了我们的假设，这表明存在一种合理的竞争性抑制机制。这些结果表明，通过DHFR靶向丝虫叶酸代谢并随之诱导凋亡可能对治疗干预有益。本研究揭示了磺酰胺查尔酮的迈克尔加成物基于结构类似物对DHFR进行竞争性抑制的新原理。
