Synthesis, biological evaluation, and molecular modeling studies of new benzoxazole derivatives as PARP-2 inhibitors targeting breast cancer

Abstract

Many benzoxazole-based and similar scaffolds were reported to have wide-range of anticancer activities. In this study, four series of benzoxazole derivatives were designed by combining benzoxazole scaffold with different amines via a reversed phenyl amide linker to produce the compounds of series A, B and C. A fourth new hybrid of benzoxazole with 1,2,3 triazole ring (series D) was also designed. The designed compounds were synthesized and screened for their anti-breast cancer activity against MDA-MB-231 and MCF-7 cell lines using MTT assay. The most potent cytotoxic compounds; 11–14, 21, 22, 25–27 were further evaluated for their in vitro PARP-2 enzyme inhibition. Compounds 12 and 27 proved to be the most active PARP-2 inhibitors with IC50 values of 0.07 and 0.057 µM, respectively. Compounds 12 and 27 caused cell cycle arrest in mutant MCF-7 cell line at G2/M and G1/S phase, respectively and they possessed significant apoptosis-promoting activity. Docking results of compounds 12 and 27 into PARP-2 pocket demonstrated binding interactions comparable to those of olaparib. Their predicted pharmacokinetic parameters and oral bioavailability appeared to be appropriate. Collectively, it could be concluded that compounds 12 and 27 are promising anti-breast cancer agents that act as PARP-2 inhibitors with potent apoptotic activity.

The anti‐breast cancer therapeutic potential of 1,2,3‐triazole‐containing hybrids

“…The majority of 1,2,3‐triazole‐benzoxazole hybrids only showed weak to moderate antiproliferative activity against breast cancer cell lines, [ 44,45 ] whereas 1,2,3‐triazole‐pyrimidine‐oxazolo[4,5‐ b ]pyridine hybrids 23 (IC 50 : 0.045–13.2 µM, MTT assay) exhibited promising activity against MCF‐7 breast cancer cells. [ 46 ] The SAR illustrated that electron‐donating group especially methoxy group was beneficial for the activity.…”

3-Pyridylvinyl benzoxazole-derived multifunctional organic materials—from solid-state photoreactivity to photophysical and electrochemical properties

“…47 Benzoxazole-containing compounds have been investigated in recent times for various applications, including investigation of solid-state molecular motion via co-crystallization, twophoton-induced blue fluorescent emission, light-mechanical energy conversion by photomechanical effects, antifungal, antibacterial, antimicrobial, as well as anticancer activity. [48][49][50][51][52][53][54][55][56][57] Benzoxazole-containing compounds have been studied for exhibiting very large Stokes shift, which are beneficial in biological applications for the reduction of chromatic aberrance and enhancing resolution. [58][59][60][61][62] Moreover, a benzoxazolefunctionalized compound was shown to be suitable for photoswitch and optical data storage devices owing to its reversible photocycloaddition reaction 63 and E-Z isomerization.…”

Advances in the synthetic strategies of benzoxazoles using 2-aminophenol as a precursor: an up-to-date review

“…It is an overarching framework of numerous biologically active compounds that are involved in synthetic, agrochemical, pharmaceutical, and material chemistry. 13,14 This skeleton is prominent in synthetic compounds and exhibits a broad range of biological activities, such as antimicrobial, 15 antitubercular, 16 antioxidant, 17 antifungal, 18 anti-inammatory, 19 anti-allergic, 20 antihyperglycemic, 21 antidepressant, 22 cytotoxic agents, 23,24 anticonvulsant, 25 and analgesic agents. 26 They are isosteres of the nucleic acid bases guanine and adenine that help them to easily interact with biological receptors in the human body.…”