Synthesis, Biological Evaluation and In Silico Studies of Some 2‐Substituted Benzoxazole Derivatives as Potential Anticancer Agents to Breast Cancer

Abstract

In an attempt to develop potent and selective anticancer agents, some 5‐ or 6‐ and N‐substituted benzoxazol‐2‐carboxamide derivatives were designed, synthesized, and evaluated for their cyclooxygenase inhibitory, antioxidant, and anti‐proliferative activity against MCF‐7 and MDA‐MB‐231 cell lines. Among them 5‐OMe, N‐piperidine substituted (compound 30), 5‐OMe, N‐4‐methylpiperidine substituted (compound 31) and 5‐Cl, N‐piperidine substituted (compound 34) benzoxazole 2‐carboxamide compounds have a moderate inhibitory effect in COX‐1 and COX‐2 enzymes. Anti‐proliferative studies show that compound 30 (IC50=5.35 μM) and compound 31 (IC50=5.82 μM) have similar activity to reference drug 5‐FU (IC50=3.95 μM) on MCF‐7 cell but they have lower toxic effect for healthy WI‐38 cell line. For the MCF‐7 cell line, compounds 30 and 31 show approximately 1.5 times higher selectivity compared to the 5‐FU control. Among the synthesized compounds 30, 31, and 34 had the best anti‐proliferative effect and were used to perform flow cytometry and cell cycle analysis on MCF‐7 cell line. To predict the binding modes and pharmacokinetic parameters of all compounds, in silico studies were carried out. These compounds may shed light on cancer treatment and cancer research.

2-Phenyl substituted Benzimidazole derivatives: Design, synthesis, and evaluation of their antiproliferative and antimicrobial activities

“…Antiproliferative activity results indicated that substituted benzimidazole derivatives positively affect the activity. Result analysis may conclude that compounds with aliphatic linkers (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55) have good to potent antiproliferative activity with high selectivity. Interestingly, the antiproliferative activity study concluded that the 2-(aryl)benzimidazole derivatives would signi cantly lead to further investigation of antiproliferative activity by changing the substituted positions and designing new linkers with different heteroatoms.…”

“…In the second group, 2-phenethylbenzimidazole derivatives (41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55), as presented in Table 2, were screened. Compound 44 was observed as the most potent antiproliferative agent against A-549 with an IC 50 value of 0.08 µM and possessed high selectivity against HEK293 with an IC 50 value of 1.00 µM, which means that it shows sixteen times more selectivity toward A549 cancer cell lines.…”

“…Also, compound 65 showed ten times more selectivity toward the A375 cell line (Table 3). Result analysis may conclude that compounds with aliphatic linkers (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55) have good to potent antiproliferative activity with high selectivity. Interestingly, the antiproliferative activities increase with the presence of chlorine atom as a mono substituent on the 5/6 position of benzimidazole compound 46 or phenyl ring compound 44.…”

Synthesis of Benzothiazole‐ and Benzoxazole‐2‐carboxamides by 2‐Chloracetamides and 2‐Amino(thio)phenols Cyclocondensation with Elemental Sulfur in Water

“…There are several methods for preparation of benzothiazole‐ or benzoxazole‐2‐carboxamides reported in literature, [6b,10] some representative examples are shown on Scheme 1. The most frequently used way to benzothiazole‐2‐carboxamides employ condensation of 2‐aminobenzenethiol with diethyl oxalate or ethyl glyoxylate, hydrolysis of ester group and amidation (or direct amidation of ethyl benzothiazole‐2‐carboxylate with amines under microwave‐assisted or thermal conditions), [6a,c,11,16] similar method can be used for synthesis of benzoxazole‐2‐carboxamides from 2‐aminophenol [9] . Reaction of 2‐bromo‐2,2‐difluoroacetic acid amides with 2‐amino(thio)phenols in presence of S 8 was utilized to obtain heterocyclic amides [17] .…”

“…The most frequently used way to benzothiazole-2carboxamides employ condensation of 2-aminobenzenethiol with diethyl oxalate or ethyl glyoxylate, hydrolysis of ester group and amidation (or direct amidation of ethyl benzothiazole-2-carboxylate with amines under microwave-assisted or thermal conditions), [6a,c,11,16] similar method can be used for synthesis of benzoxazole-2-carboxamides from 2aminophenol. [9] Reaction of 2-bromo-2,2-difluoroacetic acid amides with 2-amino(thio)phenols in presence of S 8 was utilized to obtain heterocyclic amides. [17] Another way to benzoxazole-2-carboxamides employ oxidative cyclization of 2-((2hydroxyphenyl)amino)acetamides.…”