Institute of Pharmaceutical Sciences, Kurukshetra University Kurukshetra-136119, Haryana, India.
MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala-133207, Haryana, India.
Cent Nerv Syst Agents Med Chem. 2022;22(1):39-56. doi: 10.2174/1871524922666220301121811.
Malaria parasite strains are resistant to the therapeutic effect of prophylactics medicines presently available. This resistance now poses a significant challenge to researchers to beat malaria parasitic infections. Strategies such as investigating newer hybrid chemical entities and specified drug targets may help us spot new efficient derivatives that bind to the parasites in a more specific manner and inhibit their growth.
To scientifically perform the experimental, pharmacological, and computational studies of pyrazole-based furanone hybrids as novel antimalarial agents.
A series of new furanone-based pyrazole derivatives were synthesized and investigated as potential antimalarial agents by performing in vitro antimalarial activity. To get further optimization, these synthesized derivatives were virtually screened based on ADME-T filters, and molecular docking studies were also accomplished on the crystal structures of Plasmodium falciparum lactate dehydrogenase (PfLDH). Furthermore, the in-silico prediction was supported by performing an LDH assay.
The docking data suggested that the designed hybrid of furanone-pyrazole may act as PfLDH inhibitors. It was found that the results of experimental in vitro antimalarial activity and in silico analysis correlate well to each other to a good extent. The compounds (7d), (7g), and (8e) were found to be the most potent derivatives with IC values of 1.968, 1.983, and 2.069 μg/ml, respectively.
From the results, it may be concluded that compounds that are active in low doses might be adopted as a lead compound for the development of more active antimalarial agents. The synthesized compounds (7d), (7g), and (8e) exhibited good antimalarial activity with PfLDH inhibition. The best compounds can be explored further in the future for designing the potent inhibitors of PfLDH as new potent antimalarial agents.
目前可用的预防性药物对疟原虫株的治疗效果产生了抗药性。这种抗药性现在对研究人员来说是一个重大挑战，因为它阻碍了对抗疟疾寄生虫感染的研究。例如，研究新的杂合化学实体和特定药物靶点的策略可能有助于我们发现新的有效衍生物，这些衍生物以更特异的方式与寄生虫结合并抑制其生长。
对基于吡唑的呋喃酮杂化物作为新型抗疟药物进行科学的实验、药理学和计算研究。
通过进行体外抗疟活性研究，合成了一系列新的基于呋喃酮的吡唑衍生物，并将其作为潜在的抗疟药物进行了研究。为了进一步优化，根据 ADME-T 筛选器对这些合成衍生物进行了虚拟筛选，还对恶性疟原虫乳酸脱氢酶（PfLDH）的晶体结构进行了分子对接研究。此外，还通过进行 LDH 测定来支持计算机预测。
对接数据表明，设计的呋喃酮-吡唑杂化物可能作为 PfLDH 抑制剂。发现实验体外抗疟活性和计算机分析的结果在很大程度上彼此很好地相关。化合物（7d）、（7g）和（8e）被发现是最有效的衍生物，其 IC 值分别为 1.968、1.983 和 2.069μg/ml。
从结果可以得出结论，低剂量活性化合物可能被用作开发更有效抗疟药物的先导化合物。合成的化合物（7d）、（7g）和（8e）对 PfLDH 表现出良好的抑制作用和抗疟活性。最好的化合物可以在未来进一步探索，以设计出针对 PfLDH 的有效抑制剂，作为新的强效抗疟药物。
