含嘧啶、哌嗪环的新型吲哚并[3,2-c]异喹啉衍生物的合成及其对新冠病毒主蛋白酶的生物学评价和对接研究

Synthesis of novel indolo[3,2-c]isoquinoline derivatives bearing pyrimidine, piperazine rings and their biological evaluation and docking studies against COVID-19 virus main protease.

作者信息

Verma Vaijinath A, Saundane Anand R, Meti Rajkumar S, Vennapu Dushyanth R

机构信息

Department of Chemistry, Shri Prabhu Arts, Science and J.M. Bohra Commerce, Degree College, Shorapur-585 228, Yadgir, Karnataka, India.

Department of P.G. Studies and Research in Chemistry, Gulbarga University, Kalaburagi 585106, Karnataka, India.

出版信息

J Mol Struct. 2021 Apr 5;1229:129829. doi: 10.1016/j.molstruc.2020.129829. Epub 2020 Dec 27.

A series of hybrid indolo[3,2-c]isoquinoline (δ-carboline) analogs incorporating two pyrimidine and piperizine ring frameworks were synthesized. Intending biological activities and SAR we propose replacements of fluorine, methyl and methoxy of synthetic compounds for noteworthy antimicrobial, antioxidant, anticancer and anti-tuberculosis activities. Among these compounds and were progressively strong against and . Whereas, compounds and with addition of various functional groups (OCH, CH) were excellent against and . Compound exhibited strong RSA and dynamic ferrous ion (Fe metal chelating impact with IC of 7.88 ± 0.93 and 4.06 ± 0.31 µg/mL, respectively. Compound was considerably cytotoxic against all cancer cells displaying activity better than the standard drug. Compounds and inhibited (MIC 1.0 mg/L) considerably. Molecular docking studies indicate that compounds and exhibited good interactions with 6LZE (COVID-19) and 6XFN (SARS-CoV-2) at active sites. The structure of the synthesized compounds were elementally analyzed using IR, H, C NMR and mass spectral information.

合成了一系列包含两个嘧啶和哌嗪环骨架的杂合吲哚并[3,2-c]异喹啉（δ-咔啉）类似物。基于预期的生物活性和构效关系，我们提出对合成化合物中的氟、甲基和甲氧基进行取代，以获得显著的抗菌、抗氧化、抗癌和抗结核活性。在这些化合物中，化合物[具体编号1]和[具体编号2]对[具体病菌1]和[具体病菌2]的活性逐渐增强。而添加了各种官能团（甲氧基、甲基）的化合物[具体编号3]和[具体编号4]对[具体病菌3]和[具体病菌4]表现出优异的活性。化合物[具体编号5]表现出较强的还原力（RSA）和动态亚铁离子（Fe金属螯合作用，其IC50分别为7.88 ± 0.93和4.06 ± 0.31 µg/mL）。化合物[具体编号6]对所有癌细胞都具有显著的细胞毒性，其活性优于标准药物。化合物[具体编号7]和[具体编号8]对[具体病菌5]有显著抑制作用（MIC为1.0 mg/L）。分子对接研究表明，化合物[具体编号7]和[具体编号8]在活性位点与6LZE（新冠病毒）和6XFN（新冠病毒2）表现出良好的相互作用。利用红外光谱、氢谱、碳谱和质谱信息对合成化合物的结构进行了元素分析。