The main structure of novel bromoalkyl-1,4-benzoquinones is quinoid ring that can be modified to increase the bioavailability as a drug candidate. In this research, the modifications were carried out as 2-(4-bromobutyl)-3.5-dimethyl-1,4-benzoquinone (C4), 2-(7-bromoheptyl)-3,5-dimethyl-1,4-benzoquinone (C7), and 2-(10-bromodecyl)-3.5-dimethyl-1,4-benzoquinone (C10) by bromoalkylation reaction. Target compounds were successfully synthesized in 74.72%, 11.97%, and 26.67% yield, respectively. Chemical constituents of product were identified by Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (1H-NMR and 13C-NMR), and liquid chromatography (LC)-MS. Then, synthesized compounds were investigated its properties by in vitro solubility test in octanol-water using HPLC. Solubility test results showed that the products C4, C7, and C10 had greater solubility in octanol phase than in the water phase. According to solubility assay, C4, C7, and C10 showed partition coefficients of 1.6; 4.95; 1.74 and compare to thymoquinone (positive control) partition coefficient was 2.58 at pH 7.4. Potency as drugs of synthesized compounds were evaluated by molecular docking using COX-1 (ID 1EQG) and COX-2 (ID 1CX2) as COX signaling receptor. In silico studies depicted that C7 activity has great binding affinity toward COX-1 and COX-2, respectively. Especially for the activity toward COX-1 receptor, the binding affinity of C7 was equal to Ibuprofen/native ligand (-7.7 kcal mol-1). The C7 has two molecular interactions toward COX-1, one hydrogen bond (Tyr385) and one hydrophobic (Ser530, Leu531, Ala527, Ser353, Ile523, Val349, Phe518, Leu384, Trp387, Phe381, Gly526, Tyr355, Leu359, Arg120, Val116, Tyr348). Otherwise, signaling activity of C7 toward COX-2 receptor in binding affinity showed -7.7 kcal mol-1 that slightly lower than SC-558/native ligand -11.3 kcal mol-1. Furthermore, profiling drug-target interaction between C7 and COX-1 receptor was illustrated by binding similarity. The binding similarity of C7 was 66.67%. Additionally, The Lipinski’s rule of five and the ADME parameters suggested that these compounds would have good drug-likeness.

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