In vitro and in silico assessment of antiproliferative activity of new acetamides bearing 1,3,4-oxadiazole and pyrimidine cores via COX inhibition

Abstract

Lung cancer is not only the most commonly diagnosed cancer type but also the leading cause of cancer related deaths throughout the world. The advanced methods for lung cancer therapy have focused on the development of new targeted agents. Cyclooxygenase (COX) is one of the most crucial targets for lung cancer therapy. In the current work, new compounds (1-12) containing 1,3,4-oxadiazole and pyrimidine cores within the acetamide framework were synthesized and evaluated for their cytotoxic effects on A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast (healthy) cell lines using MTT assay. Compounds 2 and 10 were defined as the most cytotoxic agents in this series (IC50 <3.9 µg/mL) compared to cisplatin (IC50= 26.00±3.00 µg/mL) without revealing cytotoxicity to healthy cells. The COX-1 and COX-2 inhibitory profiles of compounds 2 and 10 were also searched for providing a mechanistic insight into their potent antiproliferative effects. Compound 2 inhibited COX-1 and COX-2 dually and significantly (59.52% and 50.59%, respectively), whereas compound 10 exhibited no significant COX-1 and COX-2 inhibition. Molecular docking studies indicated that compound 2 showed its COX-1 and COX-2 inhibitory potencies with favourable interactions in the active sites of COX-1 and COX-2. Both in vitro and in silico assays accentuated that potential, orally bioavailable drug-like compound 2 attracted notice for the COX-targeted anti-lung cancer treatment.

New Nanostructured Materials Based on Mesoporous Silica Loaded with Ru(II)/Ru(III) Complexes with Anticancer and Antimicrobial Properties

“…The IC50 values ( Table 6 ) obtained from cell survival plots ( Figures S3–S6 ) showed that the SBA–15–RuSalen compound has the most potent antitumor efficiency, with a concentration of 23.9 μg/mL being able to inhibit half of A549 cells’ growth compared to control after 72 h. The selectivity index (the ratio between the IC 50 for normal cell line and IC 50 for the cancer cell line) for this compound was 2.4, proving the higher toxicity against tumor cells than against normal ones. By comparing the result of SBA–15–RuSalen with a positive control, such as cisplatin, the standard therapy for patients with lung cancer [ 53 ], we observed an almost-similar IC 50 value (26 ± 3.0 μg/mL), as it was previously reported [ 54 ] after 72 h of incubation of this drug with A549 cells. Furthermore, it is important to highlight that all Ru-containing hybrid materials exhibited lower IC 50 values compared to the SBA–15 compound.…”

“…The IC50 values (Table 6) obtained from cell survival plots (Figures S3-S6) showed that the SBA-15-RuSalen compound has the most potent antitumor efficiency, with a concentration of 23.9 μg/mL being able to inhibit half of A549 cells' growth compared to control after 72 h. The selectivity index (the ratio between the IC50 for normal cell line and IC50 for the cancer cell line) for this compound was 2.4, proving the higher toxicity against The IC50 values (Table 6) obtained from cell survival plots (Figures S3-S6) showed that the SBA-15-RuSalen compound has the most potent antitumor efficiency, with a concentration of 23.9 µg/mL being able to inhibit half of A549 cells' growth compared to control after 72 h. The selectivity index (the ratio between the IC 50 for normal cell line and IC 50 for the cancer cell line) for this compound was 2.4, proving the higher toxicity against tumor cells than against normal ones. By comparing the result of SBA-15-RuSalen with a positive control, such as cisplatin, the standard therapy for patients with lung cancer [53], we observed an almost-similar IC 50 value (26 ± 3.0 µg/mL), as it was previously reported [54] after 72 h of incubation of this drug with A549 cells. Furthermore, it is important to highlight that all Ru-containing hybrid materials exhibited lower IC 50 values compared to the SBA-15 compound.…”

In Vitro and In Silico Evaluation of Anticancer Activity of New Indole-Based 1,3,4-Oxadiazoles as EGFR and COX-2 Inhibitors

“…Based on these unique features, 1,3,4-oxadiazole-carrying compounds exhibit a broad biological activity spectrum, including anticancer effects. Zibotentan, with a 1,3,4-oxadiazole core, is an important anticancer agent and a lead compound for developing new 1,3,4-oxadiazole-based anticancer agents [46][47][48][49]. In a study performed by El-Sayed et al [50], novel heterocyclic oxadiazoles were synthesized and evaluated for their anticancer effects as dual selective COX-2 and EGFR inhibitors.…”