Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India.
Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Sigh Punjab Technical University, Bathinda, 151001, India.
Comb Chem High Throughput Screen. 2024;27(9):1329-1343. doi: 10.2174/1386207326666230905153443.
Cancer is a leading threat to humankind, accounting for nearly one million deaths in 2018, and the expected number of cancer-related deaths in 2040 is more than 16 million. The most common causes of cancer deaths are lung, colorectal, stomach, liver and breast cancer, while the highest number of new cancer cases belong to lung, breast, colorectal, prostate, stomach and liver cancer.
PARP-1 is an enzyme that plays an important role in DNA repair, cell propagation/survival and death due to its influence on numerous biological processes. Quinazolinones represent an important scaffold in medicinal chemistry and have a broad spectrum of biological activities.
In this study, we have synthesized quinazolinones by reaction of 2-aminobenzamide and substituted aldehydes. Molecular docking studies of synthesized compounds were performed for their PARP-1 binding affinities using Schrodinger 2016 software. ADME studies were also performed for the synthesized compounds using the QikProp tool of Schrodinger software.
Results of molecular docking studies indicated that synthesized quinazolinones had a good affinity towards active site of PARP-1 and compound 4 had the best docking score (-10.343). Results of ADME studies indicated the drug-like properties of synthesized compounds, which make them suitable drug candidates.
All the synthesized compounds have a better docking score than niraparib (-9.05). Further, the synthesized compounds have a favorable ADME profile. Therefore, they may serve as important leads in discovering PARP-1 inhibitors.
癌症是人类的主要威胁之一，2018 年造成近 100 万人死亡，预计 2040 年与癌症相关的死亡人数将超过 1600 万。癌症死亡的最常见原因是肺癌、结直肠癌、胃癌、肝癌和乳腺癌，而新癌症病例最多的是肺癌、乳腺癌、结直肠癌、前列腺癌、胃癌和肝癌。
PARP-1 是一种在 DNA 修复、细胞增殖/存活和死亡中起重要作用的酶，因为它对许多生物过程有影响。喹唑啉酮是药物化学中的一个重要支架，具有广泛的生物活性。
在这项研究中，我们通过 2-氨基苯甲酰胺和取代的醛反应合成了喹唑啉酮。使用 Schrodinger 2016 软件对合成化合物进行了分子对接研究，以评估它们与 PARP-1 的结合亲和力。还使用 Schrodinger 软件的 QikProp 工具对合成化合物进行了 ADME 研究。
分子对接研究的结果表明，合成的喹唑啉酮对 PARP-1 的活性部位具有良好的亲和力，化合物 4 具有最佳的对接评分（-10.343）。ADME 研究的结果表明，合成化合物具有类药性，这使它们成为合适的药物候选物。
所有合成的化合物的对接评分都优于尼拉帕尼（-9.05）。此外，合成的化合物具有良好的 ADME 特征。因此，它们可能成为发现 PARP-1 抑制剂的重要先导化合物。
