Quinazolinones–Phenylquinoxaline hybrids with unsaturation/saturation linkers as novel anti-proliferative agents

• Published in: Bioorganic & medicinal chemistry letters 2016-07, Vol.26 (13), p.3014-3018
• Main Authors: Palem, Jyothsna Devi, Alugubelli, Gopi Reddy, Bantu, Rajashaker, Nagarapu, Lingaiah, Polepalli, Sowjanya, Jain, S. Nishanth, Bathini, Raju, Manga, Vijjulatha
• Format: Article
• Language: English
• Subjects: Allylphenyl quinoxaline; Anti-proliferative activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer cell lines; Cell Line, Tumor; DNA - chemistry; DNA intercalates; Doxorubicin - pharmacology; Heck-cross coupling; Humans; Hydrogen Bonding; Intercalating Agents - chemical synthesis; Intercalating Agents - chemistry; Intercalating Agents - pharmacology; Molecular Docking Simulation; Paclitaxel - pharmacology; Quinazolinones; Quinazolinones - chemical synthesis; Quinazolinones - chemistry; Quinazolinones - pharmacology; Quinoxalines - chemical synthesis; Quinoxalines - chemistry; Quinoxalines - pharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.05.021

A new series of novel quinazolinones with allylphenyl quinoxaline hybrids 9a–n were efficiently synthesized in good yields by the reaction of 3-allyl-2-methylquinazolin-4(3H)-one (5a–n) with bromophenyl)quinoxaline (8) utilizing Pd catalyzed Heck-cross coupling and evaluated for anti-proliferative activity against four cancer cell lines and Docking results indicate a sign of good intercalation, suggesting that these compounds act as DNA intercalates. [Display omitted] A new series of novel quinazolinones with allylphenyl quinoxaline hybrids 9a–n were efficiently synthesized in good yields by the reaction of 3-allyl-2-methylquinazolin-4(3H)-one (5a–n) with bromophenyl)quinoxaline (8) utilizing Pd catalyzed Heck-cross coupling and evaluated for anti-proliferative activity against four cancer cell lines such as HeLa (cervical), MIAPACA (pancreatic), MDA-MB-231 (breast) and IMR32 (neuroblastoma). Compounds 9a, 9e, 9g and 9h exhibited promising anti-proliferative activity with GI50 values ranging from 0.06 to 0.2μM against four cell lines, while compounds 9e and 9k showed significant activity against HeLa and MIAPACA cell lines and compounds 9b, 9d, 9h and 9j showed selective potency against IMR32 and MDA-MB-231 cell lines. This is the first report on the synthesis and in vitro anti-proliferative evaluation of E-2-(4-substituted)-3-(3-(4-(quinoxalin-2-yl)phenyl)allyl)quinazolin-4(3H)-ones (9a–n). Docking results indicate a sign of good correlation between experimental activity and calculated binding affinity (dock score), suggesting that these compounds could act as promising DNA intercalates.