The present manuscript deals with the development of novel p-aminobenzoic acid (PABA) associated 1,3,5-triazine derivatives as antimalarial agents. The molecules were developed via microwave-assisted synthesis and structures of compounds were ascertained via numerous analytical and spectroscopic techniques. The synthesized compounds were also subjected to ADMET analysis. In a docking analysis, the title compounds showed high and diverse binding affinities towards wild (−162.45 to −369.38 kcal/mol) and quadruple mutant (−165.36 to −209.47 kcal/mol) Pf-DHFR-TS via interacting with Phe58, Arg59, Ser111, Ile112, Phe116. The in vitro antimalarial activity suggested that compounds 4e, 4b, and 4h showed IC₅₀ ranging from 4.18 to 8.66 μg/ml against the chloroquine-sensitive (3D7) strain of Plasmodium falciparum. Moreover, compounds 4g, 4b, 4e, and 4c showed IC₅₀ ranging from 8.12 to 12.09 μg/ml against chloroquine-resistant (Dd2) strain. In conclusion, our study demonstrated the development of hybrid PABA substituted 1,3,5-triazines as a novel class of Pf-DHFR inhibitor for antimalarial drug discovery.

中文翻译：

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混合 PABA-1,3,5-三嗪衍生物的微波辅助合成作为抗疟剂

本手稿涉及新型对氨基苯甲酸 (PABA) 相关 1,3,5-三嗪衍生物作为抗疟药的开发。分子是通过微波辅助合成开发的，化合物的结构是通过多种分析和光谱技术确定的。合成的化合物也进行了 ADMET 分析。在对接分析中，标题化合物通过与 Phe58、Arg59 相互作用显示出对野生（-162.45 至 -369.38 kcal/mol）和四重突变体（-165.36 至 -209.47 kcal/mol）Pf -DHFR-TS 的高且多样的结合亲和力、Ser111、Ile112、Phe116。体外抗疟活性表明化合物4e、4b和4h显示出IC₅₀范围从 4.18 到 8.66 μg/ml，对抗氯喹敏感 (3D7)恶性疟原虫菌株。此外，化合物4g、4b、4e和4c显示出针对氯喹抗性(Dd2)菌株的IC ₅₀范围为8.12至12.09 μg/ml。总之，我们的研究证明了混合 PABA 取代的 1,3,5-三嗪作为一类新型Pf- DHFR 抑制剂的开发，用于抗疟药物的发现。