Mokale Santosh, Lokwani Deepak, Mujaheed Abdul
Dr. Rafiq Zakaria Campus, Y.B. Chavan College of Pharmacy, Aurangabad, Maharashtra, India.
Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, 425405, Maharashtra, India.
Curr HIV Res. 2021;19(6):535-547. doi: 10.2174/1570162X19666210915102230.
This paper reports the synthesis, Non-nucleoside reverse transcriptase inhibitory (NNRTIs) activity and computational studies of 2-((4-chloro-2-subtitutedphenoxy) methyl)-4-(furan-2-ylmethylene)-1-substituted Pyridine/-pyrimidine-1H-imidazol-5(4H)-ones.
The imidazol-5-one analogs were synthesized by conventional method and characterized by FT-IR, NMR and mass spectral data. All compounds were evaluated for in-vitro NNRTI activity by using reverse transcriptase (RT) assay kit (Roche). The in-silico docking studies were conducted on RT enzyme to investigate binding site interactions of synthesized compounds. The MMGBSA method was also used to calculate the binding free energy between the inhibitors and RT enzyme. The MD simulation was further performed for the apo form of the RT enzyme and docked complex of compound A6-RT enzyme to better understand the stability of the protein-ligand complex.
The bioactivity analysis revealed that most of the synthesized compounds showed significant inhibitory activity against RT enzyme and the IC50 value was found to be in the range of 1.76-3.88 μM. The computational studies suggest that the docked compounds form the H-bonding with amino acid residue Lys101 and hydrophobic interactions with amino acid residues Tyr188, Tyr181, Trp229, and Tyr318, which act as the primary driving forces for protein-ligand interaction.
The reported imidazol-5-one analogs can act as lead for further development of prospective RT inhibitors.
本文报道了2-((4-氯-2-取代苯氧基)甲基)-4-(呋喃-2-基亚甲基)-1-取代吡啶/-嘧啶-1H-咪唑-5(4H)-酮的合成、非核苷类逆转录酶抑制（NNRTIs）活性及计算研究。
通过常规方法合成咪唑-5-酮类似物，并通过傅里叶变换红外光谱（FT-IR）、核磁共振（NMR）和质谱数据进行表征。使用逆转录酶（RT）检测试剂盒（罗氏公司）对所有化合物进行体外NNRTI活性评估。对RT酶进行计算机模拟对接研究，以研究合成化合物的结合位点相互作用。还使用MMGBSA方法计算抑制剂与RT酶之间的结合自由能。对RT酶的无配体形式和化合物A6-RT酶的对接复合物进一步进行分子动力学（MD）模拟，以更好地理解蛋白质-配体复合物的稳定性。
生物活性分析表明，大多数合成化合物对RT酶显示出显著的抑制活性，IC50值在1.76 - 3.88 μM范围内。计算研究表明，对接的化合物与氨基酸残基Lys101形成氢键，并与氨基酸残基Tyr188、Tyr181、Trp229和Tyr318形成疏水相互作用，这些相互作用是蛋白质-配体相互作用的主要驱动力。
所报道的咪唑-5-酮类似物可作为进一步开发潜在RT抑制剂的先导化合物。
