Design, synthesis, molecular docking studies and biological evaluation of thiazole carboxamide derivatives as COX inhibitors

Hawash, Mohammed
Jaradat, Nidal
Abualhasan, Murad
Qaoud, Mohammed T.
Kahraman, Deniz Cansen
Daraghmeh, Heba
Maslamani, Leen
Sawafta, Mais
Ratrout, Ala
Issa, Linda
Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been the most commonly used class of medications worldwide for the last three decades. Objectives: This study aimed to design and synthesize a novel series of methoxyphenyl thiazole carboxamide derivatives and evaluate their cyclooxygenase (COX) suppressant and cytotoxic properties. Methods: The synthesized compounds were characterized using 1H, 13C-NMR, IR, and HRMS spectrum analysis and were evaluated for their selectivity towards COX-1 and COX-2 using an in vitro COX inhibition assay kit. Besides, their cytotoxicity was evaluated using the Sulforhodamine B (SRB) assay. Moreover, molecular docking studies were conducted to identify the possible binding patterns of these compounds within both COX-1 and COX-2 isozymes, utilizing human X-ray crystal structures. The density functional theory (DFT) analysis was used to evaluate compound chemical reactivity, which was determined by calculating the frontier orbital energy of both HOMO and LUMO orbitals, as well as the HOMO–LUMO energy gap. Finally, the QiKProp module was used for ADME-T analysis. Results: The results revealed that all synthesized molecules have potent inhibitory activities against COX enzymes. The percentage of inhibitory activities at 5 µM concentration against the COX2 enzyme was in the range of 53.9–81.5%, while the percentage against the COX-1 enzyme was 14.7–74.8%. That means almost all of our compounds have selective inhibition activities against the COX-2 enzyme, and the most selective compound was 2f, with selectivity ratio (SR) value of 3.67 at 5 µM concentration, which has a bulky group of trimethoxy on the phenyl ring that could not bind well with the COX-1 enzyme. Compound 2h was the most potent, with an inhibitory activity percentage at 5 µM concentration of 81.5 and 58.2% against COX-2 and COX-1, respectively. The cytotoxicity of these compounds was evaluated against three cancer cell lines: Huh7, MCF-7, and HCT116, and negligible or very weak activities were observed for all of these compounds except compound 2f, which showed moderate activities with IC50 values of 17.47 and 14.57 µM against Huh7 and HCT116 cancer cell lines, respectively. Analysis of the molecular docking suggests 2d, 2e, 2f, and 2i molecules were bound to COX-2 isozyme favorably over COX-1 enzyme, and their interaction behaviors within COX-1 and COX-2 isozymes were comparable to celecoxib, as an ideal selective COX-2 drug, which explained their high potency and COX-2 selectivity. The molecular docking scores and expected affinity using the MM-GBSA approach were consistent with the recorded biological activity. The calculated global reactivity descriptors, such as HOMO and LUMO energies and the HOMO–LUMO gaps, confirmed the key structural features required to achieve favorable binding interactions and thus improve affinity. The in silico ADME-T studies asserted the druggability of molecules and have the potential to become lead molecules in the drug discovery process. Conclusion: In general, the series of the synthesized compounds had a strong effect on both enzymes (COX-1 and COX-2) and the trimethoxy compound 2f was more selective than the other compounds.
BMC Chemistry


Structural and functional characterization of simvastatin-induced myotoxicity in different skeletal muscles
Ozek, Nihal Simsek; Bal, I. Burak; SARA, MEHMET YILDIRIM; Onur, Rustu; Severcan, Feride (Elsevier BV, 2014-01-01)
Background: Statins are the most commonly used drugs for the treatment of hypercholesterolemia. Their most frequent side effect is myotoxicity. To date, it remains unclear whether statins preferentially induce myotoxicity in fast- or in slow-twitch muscles. Therefore, we investigated these effects on fast- (extensor digitorum longus; EDL), slow- (soleus; SOL), and mixed-twitch muscles (diaphragm; DIA) in rats by comparing their contractile and molecular structural properties.
Functional Application Of İmmununoliposomes Encapsulating Celecoxib On Colon Cancer Cell Lines.
Banerjee, Sreeparna(2010-12-31)
Long term regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been correlated with reduced risk of variety of cancers. Celecoxib is a new generation NSAID that can selectively inhibit activity of cyclooxygenase-2 (COX-2) Celecoxib serves as a chemopreventive agent in colorectal cancer. Therefore there is growing interest in developing drug delivery systems for celecoxib, Targeting will be carried out by conjugation of a chimeric monoclonal antibody (Cetuximab) against the Epidermal Growth Fac...
Design and characterization of capsaicin loaded nanoemulsions
Akbaş, Elif; Öztop, Halil Mecit; Söyler, Ulviye Betül; Department of Food Engineering (2016)
In recent years, nanoemulsion based systems have been successfully used in food, medical and pharmaceutical applications as effective lipophilic carrier systems for nutraceuticals, drugs, antioxidants and antimicrobial agents. The primary active ingredient of chili pepper, capsaicin is a hydrophobic substance and was proved to be a compound showing good antimicrobial activity against various microorganisms. The aim of the proposed study was to prepare and characterize capsaicin loaded nanoemulsion systems. ...
Differential gene expression analysis related to extracellular matrix components in drug-resistant RPMI-8226 cell line
Mutlu, Pelin; Gündüz, Ufuk (Elsevier BV, 2012-4)
Drug resistance remains a major obstacle to the successful use of chemotherapeutic drugs for many types of cancers including multiple myeloma. It is becoming increasingly apparent that tumor microenvironment could provide a shelter to malignant plasma cells that allow their survival after initial drug exposure. This study demonstrates alterations in gene expression levels of several extracellular matrix (ECM) components in prednisone, vincristine and melphalan-resistant RPMI-8226 myeloma cells. Resistant RP...
Investigation Of Nsaıd Lipid İnteractions Membranes Via Spectroscopic And Themoanalytical Techniques.
Banerjee, Sreeparna(2011-12-31)
Long term regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been correlated with reduced risk of variety of cancers. Celecoxib is a new generation NSAID that can selectively inhibit activity of cyclooxygenase-2 (COX-2) enzyme in prostaglandin production pathway The anticarcinogenic effects of Celecoxib are not solely due to the inhibition of COX-2. COX-2 independent effects observed in vitro can be summarized as inhibition of cell cycle progression, induction of apoptosis, and inhibition of ...
Citation Formats
M. Hawash et al., “Design, synthesis, molecular docking studies and biological evaluation of thiazole carboxamide derivatives as COX inhibitors,” BMC Chemistry, vol. 17, no. 1, pp. 0–0, 2023, Accessed: 00, 2023. [Online]. Available: