CHARACTERIZATION AND MOLECULAR DOCKING OF CINNAMIC ACID DERIVATIVES: POTENTIAL INHIBITORS OF CYCLOOXYGENASE ENZYMES SAMUEL J BUNU 1 * , DEGHINMOTEI ALFRED-UGBENBO 2 , OYEINTONBARA MIEDIEGHA 1 , HARUNA BABA 3 1 Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy, Niger Delta University, Wilberforce Island, Bayelsa, Nigeria, 2 Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Bayelsa Medical University, Yenagoa, Bayelsa, Nigeria, 3 Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy, University of Calabar, Calabar, Cross River State, Nigeria. E-mail: pharmsamuelbunu@gmail.com Received: 26 September 2023, Revised and Accepted: 12 October 2023 ABSTRACT Objective: The pathology of every disease passes through the inflammation stage; hence, the design and optimization of potential lead compounds as anti-inflammatory agents is still a significant part of medicinal chemistry globally. Methods: In this study, we designed, synthesized, and characterized some cinnamic acid derivatives and performed molecular docking of the derivatives on the human cyclooxygenase-1 (COX-1) enzyme. Results: The elemental analysis showed the presence of different functional groups. Molecular docking was performed on the active sites of COX-1 (PDB ID: 6Y3C). The derivatives as well as the standard compound, were observed to interact mainly with the arginine residue of the target protein. The dioxomethylene substituted derivative showed the highest binding affinity, compared with other derivatives, including the standard drug (−6.8 kcal/mol). Conclusion: The binding affinity observed in the cinnamic derivatives, and biological activities correlations revealed that compounds with the dioxomethylene group would be good anti-inflammatory lead molecules, as they demonstrated high affinity to the target protein and biological activities. Thus, these compounds can serve as potential lead compounds for the design, and development of effective anti-inflammatory agents, targeted to inhibit the human COX-1 enzyme involved in biological inflammatory mechanisms. Keywords: Anti-inflammatory, Inflammation, Cinnamic acid, Cyclooxygenase, Molecular docking. INTRODUCTION Cinnamic acid (Fig. 1) is a natural aromatic carboxylic acid and a key chemical constituent found in Cinnamomum cassia (Chinese cinnamon) and Panax ginseng, as well as some fruits, vegetables, and honey [1]. Cinnamic acid derivatives possess antimicrobial, management of cancer, down-regulation of blood glucose levels in diabetes, and are useful in neurological disorders [2]. Some derivatives of cinnamic acid have been severally reported to be as effective as the conventional medications used in the management of different disease conditions in vitro, thereby making these compounds very significant potential therapeutic remedies [2]. The presence of an acrylic acid group substituted on the phenyl ring of cinnamic acid gives the compound either a cis- or trans- configuration [3,4]. Cinnamic acid derivatives activate the peroxisome proliferator-activated receptor-α, thereby stimulating lysosomal biogenesis and lowering amyloid protein aggregation (plaque) observed in Alzheimer’s disease in mice [1]. Because of its natural origin, cinnamic acid and its derivatives are believed to have minimal side effects on biological tissues [3]; hence, the use of cinnamic acid derivatives’ inflammatory properties was evaluated, to find alternative medicines that could be useful in the pharmacotherapy of inflammatory diseases [5]. The mechanism of action of most anti-inflammatory agents, especially, the non-steroidal anti-inflammatory drugs (NSAIDs) with analgesic and antipyretic activity, is the inhibition of the cyclooxygenase (COX-1 or COX-2) enzymes. These enzymes are responsible for the biosynthesis of prostaglandins and thromboxane [6]. Abnormalities in prostaglandin and thromboxane metabolism may contribute to the pathophysiology of several disease conditions including hypertension, pyrexia, pain regulation, and inflammation [7]. The inflammatory process is the initial phase of disease progression [8], making anti-inflammatory agents useful in almost every unusual clinical symptom. NSAIDs delay the progression of Alzheimer’s disease, pointing to their potential in the inhibition of amyloid protein aggregation, which has also been shown by some cinnamic acid derivatives [1,9]. Some NSAIDs are known to cause severe neuroinflammation, gastritis, gastric ulcer, and even stomach cancer [10,11]. Structure-activity relationships (SAR) show the relationships between the physicochemical properties of chemical compounds and have been used severally in the design and development of medicinal agents and quantification of their biotransformation processes. A more elaborate quantitative-SAR (QSAR) helps to obtain a reliable statistical model for the prediction of the pharmacological activities of the samples under analysis [12], including hydrophobicity, hydrophilicity, and the nature of plasma binding of drug molecules [13,14]. Following these complications, the design and development of less toxic, effective, and stable analgesic and anti-inflammatory agents are imminent. This study utilized SAR and molecular docking of some synthesized cinnamic acid derivatives, previously evaluated pharmacologically and characterized using nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FTIR), to quantify their COX-1 enzymes binding affinity and comparative anti-inflammatory activity with diclofenac (NSAIDs), as potential lead compounds for the design and discovery of therapeutically useful anti-inflammatory agents. METHODS Synthesis Five derivatives of cinnamic acid were successfully synthesized. Malonic acid and derivatives of benzaldehydes were used in the Research Article Vol 11, 2023 ISSN - 2321-550X © 2023 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ijls.2023v11i1.49501. Journal homepage: https://innovareacademics.in/journals/index.php/ijls