Design, synthesis, and computational studies on dihydropyrimidine scaffolds as potential lipoxygenase inhibitors and cancer chemopreventive agents

Katharigatta N Venugopala,1,2 Reshme Govender,2 Mohammed A Khedr,1,3 Rashmi Venugopala,4 Bandar E Aldhubiab,1 Sree Harsha,1 Bharti Odhav2 1Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Kingdom of Saudi Arabia; 2Department of Biotechnology and Food Technology, Durban University of Technology, Durban, South Africa; 3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ein Helwan, Cairo, Egypt; 4Department of Public Health Medicine, University of KwaZulu-Natal, Howard College Campus, Durban, South Africa Abstract: Dihydropyrimidine scaffold has a wide range of potential pharmacological activities such as antiviral, antitubercular, antimalarial, anti-inflammatory, and anticancer properties. 5-Lipoxygenase enzyme is an enzyme responsible for the metabolism of arachidonic acid to leukotrienes. The elevated levels of this enzyme and its metabolites in cancer cells have a direct relation on the development of cancer when compared to normal cells. The development of novel lipoxygenase inhibitors can have a major role in cancer therapy. A series of substituted 1,4-dihydropyrimidine analogues were synthesized and characterized by 1H-NMR, 13C-NMR, and HRMS. Molecular docking against lipoxygenase enzyme (protein data bank code =3V99) was done using Molecular Operating Environment 2013.08 and Leadit 2.1.2 softwares and showed high affinities. The synthesized compounds were tested for their lipoxygenase inhibitory activity and showed inhibition ranging from 59.37%±0.66% to 81.19%±0.94%. The activity was explained by a molecular docking study. The title compounds were also tested for cytotoxic activity against two human cancer cell lines Michigan Cancer Foundation-7 and human melanoma cells and a normal peripheral blood mononuclear cell line. Keywords: 1,4-dihydropyrimidines, synthesis and characterization, molecular docking study