Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, Louisiana, USA.
Arch Pharm (Weinheim). 2021 Dec;354(12):e2100281. doi: 10.1002/ardp.202100281. Epub 2021 Sep 29.
Globally, lung cancer and tuberculosis are considered to be very serious and complex diseases. Evidence suggests that chronic infection with tuberculosis (TB) can often lead to lung tumors; therefore, developing drugs that target both diseases is of great clinical significance. In our study, we designed and synthesized a suite of 14 new quinazolinones (5a-n) and performed biological investigations of these compounds in Mycobacterium tuberculosis (MTB) and cancer cell lines. In addition, we conducted a molecular modeling study to determine the mechanism of action of these compounds at the molecular level. Compounds that showed anticancer activity in the preliminary screening were further evaluated in three cancer cell lines (A549, Calu-3, and BT-474 cells) and characterized in an epidermal growth factor receptor (EGFR) binding assay. Cytotoxicity in noncancerous lung fibroblast cells was also evaluated to obtain safety data. Our theoretical and experimental studies indicated that our compounds showed a mechanism of action similar to that of erlotinib by inhibiting the EGFR tyrosine kinase. In turn, the antituberculosis activity of these compounds would be produced by the inhibition of enoyl-ACP-reductase. From our findings, we were able to identify two potential lead compounds (5i and 5l) with dual activity and elevated safety toward noncancerous lung fibroblast cells. In addition, our data identified three compounds with excellent anti-TB activities (compounds 5i, 5l, and 5n).
在全球范围内，肺癌和结核病被认为是非常严重和复杂的疾病。有证据表明，慢性结核分枝杆菌（TB）感染通常会导致肺部肿瘤；因此，开发针对这两种疾病的药物具有重要的临床意义。在我们的研究中，我们设计并合成了一系列 14 种新的喹唑啉酮（5a-n），并对这些化合物在结核分枝杆菌（MTB）和癌细胞系中的生物活性进行了研究。此外，我们还进行了分子模拟研究，以确定这些化合物在分子水平上的作用机制。在初步筛选中表现出抗癌活性的化合物在三种癌细胞系（A549、Calu-3 和 BT-474 细胞）中进行了进一步评估，并在表皮生长因子受体（EGFR）结合测定中进行了表征。还评估了对非癌性肺成纤维细胞的细胞毒性，以获得安全性数据。我们的理论和实验研究表明，我们的化合物通过抑制 EGFR 酪氨酸激酶表现出与厄洛替尼相似的作用机制。反过来，这些化合物的抗结核活性将通过抑制烯酰基辅酶 A 还原酶产生。根据我们的研究结果，我们能够确定两种具有双重活性和对非癌性肺成纤维细胞安全性提高的潜在先导化合物（5i 和 5l）。此外，我们的数据还确定了三种具有优异抗结核活性的化合物（化合物 5i、5l 和 5n）。
