Alkhaldi Abdulsalam A M, Al-Sanea Mohammad M, Nocentini Alessio, Eldehna Wagdy M, Elsayed Zainab M, Bonardi Alessandro, Abo-Ashour Mahmoud F, El-Damasy Ashraf K, Abdel-Maksoud Mohammed S, Al-Warhi Tarfah, Gratteri Paola, Abdel-Aziz Hatem A, Supuran Claudiu T, El-Haggar Radwan
Biology Department, College of Science, Jouf University, Sakaka, Aljouf, 72341, Saudi Arabia.
Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia.
Eur J Med Chem. 2020 Dec 1;207:112745. doi: 10.1016/j.ejmech.2020.112745. Epub 2020 Aug 22.
Herein we describe design and synthesis of different series of novel small molecules featuring 3-methylthiazolo[3,2-a]benzimidazole moiety (as a tail) connected to the zinc anchoring benzenesulfonamide moiety via ureido (7), enaminone (12), hydrazone (14), or hydrazide (15) linkers. The newly prepared conjugates have been screened for their inhibitory activities toward four human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms: hCA I, II, IX and XII. Thereafter, the urea and enaminone linkers were elongated by one- or two-atoms spacers to afford the elongated counterparts 9 and 13, respectively. Finally, the zinc anchoring sulfonamide group was replaced by the carboxylic acid group to afford acids 17. Compounds 12d, 13b and 15 displayed single-digit nanomolar CA IX inhibitory activities (Ks = 6.2, 9.7 and 5.5 nM, respectively), along with good selectivity towards hCA IX over hCA I and II. Subsequently, they were screened for their growth inhibitory actions against breast cancer MCF-7 and MDA-MB-231 cell lines, and for their impact on cell cycle progression and induction of apoptosis. Moreover, a molecular docking study was conducted to gain insights for the plausible binding interactions of target sulfonamides within hCA isoforms II, IX and XII binding sites.
在此，我们描述了不同系列新型小分子的设计与合成，这些小分子具有通过脲基（7）、烯胺酮（12）、腙（14）或酰肼（15）连接子连接到锌锚定苯磺酰胺部分的3 - 甲基噻唑并[3,2 - a]苯并咪唑部分（作为尾部）。新制备的缀合物已针对四种人类（h）碳酸酐酶（CA，EC 4.2.1.1）同工型：hCA I、II、IX和XII进行了抑制活性筛选。此后，脲基和烯胺酮连接子通过一原子或两原子间隔基进行延长，分别得到延长后的对应物9和13。最后，锌锚定磺酰胺基团被羧酸基团取代，得到酸17。化合物12d、13b和15表现出个位数纳摩尔的CA IX抑制活性（Ks分别为6.2、9.7和5.5 nM），并且对hCA IX相对于hCA I和II具有良好的选择性。随后，对它们针对乳腺癌MCF - 7和MDA - MB - 231细胞系的生长抑制作用以及对细胞周期进程和细胞凋亡诱导的影响进行了筛选。此外，进行了分子对接研究，以深入了解目标磺酰胺在hCA同工型II、IX和XII结合位点内可能的结合相互作用。
