Molecular docking, toxicity study and in vitro antimalarial evaluation of pyrazole substituted 1,3,5-triazine derivatives

IF 1.4 4区医学 Q3 PARASITOLOGY

Experimental parasitology Pub Date : 2025-04-23 DOI:10.1016/j.exppara.2025.108945

Bonita Chetia , Anshul Shakya , Surajit Kumar Ghosh , Sathishkumar Vinayagam , Saurav Jyoti Patgiri , Ipsita Pal Bhowmick , Udaya Pratap Singh , Hans Raj Bhat

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Abstract

The development of resistance to antimalarial drugs such as chloroquine, amodiaquine, artemisinin, and antifolates is a major health concern, prompting more research into new antimalarial therapies. In the present study, we intend to develop pyrazole substituted 1,3,5-triazine derivatives 7(a-j) as antimalarial agents. These compounds were synthesized using conventional methods and analyzed using various spectroscopic techniques. The docking results showed that compounds 7j and 7i exhibited an excellent binding interactions with PRO A:113, ILE A:164, SER A:111, PHE A:58, LEU A:46, LEU A:119, VAL A:45, ILE A:112 (−204.97to −118.41 kcal/mol) and TYR A:170, CYS A:15, PRO A:113, ILE A:112, ALA A:16, PHE A:58, MET A:55, SER A:111 (−216.24to −152.06 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR-TS. Compounds 7j and 7i exhibited considerable antimalarial efficacy against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of P. falciparum, with IC₅₀ values ranging from 23.78 to 83.36 μM and 30.89–64.24 μM, respectively. These pyrazole-substituted 1,3,5-triazine derivatives could be utilized to find a novel class of Pf-DHFR-TS inhibitors.

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吡唑取代1,3,5-三嗪衍生物的分子对接、毒性研究及体外抗疟评价

对氯喹、阿莫地喹、青蒿素和抗叶酸等抗疟药物产生耐药性是一个主要的健康问题，促使人们对新的抗疟疗法进行更多的研究。在本研究中，我们打算开发吡唑取代的1,3,5-三嗪衍生物7（a-j）作为抗疟药。这些化合物使用常规方法合成，并使用各种光谱技术进行分析。对接结果表明，化合物7j和7i与PRO A:113、ILE A:164、SER A:111、PHE A:58、LEU A:46、LEU A:119、VAL A:45、ILE A:112（−204.97 ~−118.41 kcal/mol）和TYR A:170、CYS A:15、PRO A:113、ILE A:112、ALA A:16、PHE A:58、MET A:55、SER A:111（−216.24 ~−152.06 kcal/mol）对野生型（1J3I）和四倍突变型（1J3K） pfdhfr - ts表现出良好的结合作用。化合物7j和7i对氯喹敏感型（3D7）和耐药型（Dd2）恶性疟原虫具有较强的抗疟活性，IC50值分别为23.78 ~ 83.36 μM和30.89 ~ 64.24 μM。这些吡唑取代的1,3,5-三嗪衍生物可以用来寻找一类新的pfdhfr - ts抑制剂。

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来源期刊

Experimental parasitology 医学-寄生虫学

CiteScore

3.10

自引率

4.80%

发文量

160

审稿时长

3 months

期刊介绍： Experimental Parasitology emphasizes modern approaches to parasitology, including molecular biology and immunology. The journal features original research papers on the physiological, metabolic, immunologic, biochemical, nutritional, and chemotherapeutic aspects of parasites and host-parasite relationships.