Malaria has been a source of concern for humans for millennia; therefore in the present study we have utilized in-silico approach to generate diverse anti-malarial hit. Towards this, Molinspiration cheminformatics and Biovia Discovery Studio (DS) 2020 were used to conduct molecular modelling studies on 120 designed compounds. Furthermore, the TOPKAT module was used to evaluate the toxicity of the screened compounds. The CDOCKER docking technology was used to investigate protein–ligand docking against the Pf-DHFR-TS protein (PDB ID: 1J3I and 1J3K). These compounds were synthesized using a conventional and microwave-assisted nucleophilic substitution reaction, and they were characterized using a variety of physicochemical and spectroscopic methods. Among the ten compounds tested, Df3 had the highest antimalarial activity against the chloroquine-resistant (Dd2) strain, with an IC₅₀ value of 9.54 μg mL⁻¹ and further demonstrate, molecular dynamics (MD) simulation studies and estimation of MM-PBSA-based free binding energies of docked complexes with 1J3I and 1J3K were carried out. The discovery of a novel class of Pf-DHFR inhibitors can be accomplished using this hybrid scaffold.

几千年来，疟疾一直是人类关注的问题。因此，在本研究中，我们利用计算机模拟方法来产生多种抗疟药。为此，Molinspiration 化学信息学和 Biovia Discovery Studio (DS) 2020 被用于对 120 种设计的化合物进行分子建模研究。此外，TOPKAT 模块用于评估筛选化合物的毒性。CDOCKER 对接技术用于研究针对Pf-的蛋白质-配体对接DHFR-TS 蛋白（PDB ID：1J3I 和 1J3K）。这些化合物是使用常规和微波辅助的亲核取代反应合成的，并使用各种物理化学和光谱方法对其进行了表征。在测试的十种化合物中，Df3 对氯喹抗性 (Dd2) 菌株具有最高的抗疟活性，IC ₅₀值为 9.54 μg mL ^-1并进一步证明，分子动力学 (MD) 模拟研究和 MM-PBSA 的估计进行了基于 1J3I 和 1J3K 的对接复合物的自由结合能。使用这种混合支架可以发现一类新型Pf- DHFR 抑制剂。