Identification of Novel Cyclooxygenase-1 Selective Inhibitors of Thiadiazole-Based Scaffold as Potent Anti-Inflammatory Agents with Safety Gastric and Cytotoxic Profile
Michelyne Haroun,
Maria Fesatidou,
Anthi Petrou,
Christophe Tratrat,
Panagiotis Zagaliotis,
Antonis Gavalas,
Katharigatta N. Venugopala,
Hafedh Kochkar,
Promise M. Emeka,
Nancy S. Younis,
Dalia Ahmed Elmaghraby,
Mervt M. Almostafa,
Muhammad Shahzad Chohan,
Ioannis S. Vizirianakis,
Aliki Papadimitriou-Tsantarliotou,
Athina Geronikaki
Affiliations
Michelyne Haroun
Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
Maria Fesatidou
School of Pharmacy, Aristotle, University of Thessaloniki, 54124 Thessaloniki, Greece
Anthi Petrou
School of Pharmacy, Aristotle, University of Thessaloniki, 54124 Thessaloniki, Greece
Christophe Tratrat
Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
Panagiotis Zagaliotis
School of Pharmacy, Aristotle, University of Thessaloniki, 54124 Thessaloniki, Greece
Antonis Gavalas
School of Pharmacy, Aristotle, University of Thessaloniki, 54124 Thessaloniki, Greece
Katharigatta N. Venugopala
Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
Hafedh Kochkar
Department of Chemistry, College of Science, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
Promise M. Emeka
Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
Nancy S. Younis
Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
Dalia Ahmed Elmaghraby
Department of Pharmacy Practice, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
Mervt M. Almostafa
Department of Chemistry, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia
Muhammad Shahzad Chohan
Biomedical Sciences Department, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
Ioannis S. Vizirianakis
Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Aliki Papadimitriou-Tsantarliotou
Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Athina Geronikaki
School of Pharmacy, Aristotle, University of Thessaloniki, 54124 Thessaloniki, Greece
Major obstacles faced by the use of nonsteroidal anti-inflammatory drugs (NSAID) are their gastrointestinal toxicity induced by non-selective inhibition of both cyclooxygenases (COX) 1 and 2 and their cardiotoxicity associated with a certain class of COX-2 selective inhibitors. Recent studies have demonstrated that selective COX-1 and COX-2 inhibition generates compounds with no gastric damage. The aim of the current study is to develop novel anti-inflammatory agents with a better gastric profile. In our previous paper, we investigated the anti-inflammatory activity of 4-methylthiazole-based thiazolidinones. Thus, based on these observations, herein we report the evaluation of anti-inflammatory activity, drug action, ulcerogenicity and cytotoxicity of a series of 5-adamantylthiadiazole-based thiazolidinone derivatives. The in vivo anti-inflammatory activity revealed that the compounds possessed moderate to excellent anti-inflammatory activity. Four compounds 3, 4, 10 and 11 showed highest potency (62.0, 66.7, 55.8 and 60.0%, respectively), which was higher than the control drug indomethacin (47.0%). To determine their possible mode of action, the enzymatic assay was conducted against COX-1, COX-2 and LOX. The biological results demonstrated that these compounds are effective COX-1 inhibitors. Thus, the IC50 values of the three most active compounds 3, 4 and 14 as COX-1 inhibitors were 1.08, 1.12 and 9.62 μΜ, respectively, compared to ibuprofen (12.7 μΜ) and naproxen (40.10 μΜ) used as control drugs. Moreover, the ulcerogenic effect of the best compounds 3, 4 and 14 were evaluated and revealed that no gastric damage was observed. Furthermore, compounds were found to be nontoxic. A molecular modeling study provided molecular insight to rationalize the COX selectivity. In summary, we discovered a novel class of selective COX-1 inhibitors that could be effectively used as potential anti-inflammatory agents.
