Evaluation of Ethylated Phenylcarbamoylazinane‐1,2,4‐Triazole Amides Derivatives as 15‐Lipoxygenase Inhibitors Together with Cytotoxic, ADME and Molecular Modeling Studies

Abstract

AbstractSearching the organic compound as anti‐inflammatory agent is a fruitful effort to treat inflammatory disorders such as asthma, arthritis, psoriasis, and especially cancer. These disorders can be cured by lipoxygenase (LOX) inhibitors, which have the ability to stop the development and progression of inflammation. The present research described the synthesis of fifteen new N‐alkyl/aralkyl/aryl derivatives (7 a–o) of 2‐(4‐ethyl‐5‐(1‐phenylcarbamoyl)piperidine‐4H‐1,2,4‐triazol‐3‐ylthio)acetamide by the continuous conversions of ethyl piperidine‐4‐carboxylate (a) into phenylcarbamoyl derivative (1) hydrazide (2), semicarbazide (3) and finally the N‐ethylated 5‐(1‐phenylcarbamoyl)piperidine‐1,2,4‐triazole (4). The target molecules (7 a–o) were formed by the reaction of 4 with various electrophiles (6 a–o), in methanolic potassium hydroxide. These synthetic analogues were characterized by FTIR, 1H, 13C NMR spectroscopy, EIMS, and HREIMS spectrometry. The compounds 7 a–o were screened for their inhibitory potential against 15‐lipoxygenase. Compounds 7 b, 7 e, 7 c and 7 g displayed the potent inhibitory potential (IC50 17.52±0.67, 35.61±0.81, 36.24±0.83 & 36.52±0.58 μM, respectively), whereas, moderate inhibition was shown by 7 h, 7 a, 7 d with IC50 values between 42.95±0.73 to 45.67±0.75 μM, respectively. Some compounds exhibited drug‐like characteristics due to their lower cytotoxic and good ADME profiles and supported by molecular modeling studies where one of the NH groups was found engaged through hydrogen bonding with Ala672. The carbonyl group amide and Asn554 were connected by a hydrogen bond, whereas the second NH group was also linked through hydrogen bonds with Gln363.