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 stud

Nanoparticle formulation by Büchi B-90 Nano Spray Dryer for oral mucoadhesion

Sree N Harsha,1 Bander E Aldhubiab,1 Anroop B Nair,1 Ibrahim Abdulrahman Alhaider,1 Mahesh Attimarad,1 Katharigatta N Venugopala,1  Saminathan Srinivasan,2 Nagesh Gangadhar,2 Afzal Haq Asif3 1Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia; 2Department of Pharmaceutics, East Point College of Pharmacy, Bangalore, India; 3Department of Pharmacy Practice, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia Abstract: Diabetes is considered one of the main threats to global public health in this era. It is increasing rapidly in every part of the world; the prevalence of the disease will grow to the point where 366 million people will be affected by 2030. The prevalence of diabetes mellitus (DM) in the Saudi population is high, and the majority of patients suffer from type 2 DM. Marketed oral antidiabetic drugs have indicated poor tolerability during chronic treatments, and this contributes to the moderately large proportion of type 2 DM patients that remain inadequately managed. Vildagliptin nanospheres were prepared with aminated gelatin using a spray-drying method; narrow particle-size distribution was seen at 445 nm. The angle of repose was found to be θ <33.5°. The nanospheres appeared to be spherical with a smooth surface. The drug content and percentage yield of the nanospheres were found to be 76.2%±4.6% and 83%±2%, respectively. The nanosphere-swell profile was found to be 165%±7%. The pure drug was 100% dissolved in 30 minutes, and the nanosphere formulation took 12 hours to dissolve (97.5%±2%), and followed a Korsmeyer–Peppas kinetic model with an R2 of 0.9838. The wash-off test of nanospheres found that they exhibited an excellent mucoadhesive property at 86.7% for 8 hours. The stability-study data showed no changes in the physicochemical properties of the nanospheres, and suggested that the nanospheres be stored below room temperature. The amount of vildagliptin retained was 1.6% within 3 hours, and in comparison with the gelatin vildagliptin nanoparticles formulation, the percentage that was retained was much higher (98.2% in 12 hours). Keywords: nanospheres, vildagliptin, Büchi Nano Spray Dryer, diabete

Design, synthesis, and characterization of (1-(4-aryl)-1H-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates against Mycobacterium tuberculosis

Katharigatta N Venugopala,1,2 G B Dharma Rao,3 Subhrajyoti Bhandary,3 Melendhran Pillay,4 Deepak Chopra,3 Bandar E Aldhubiab,1 Mahesh Attimarad,1 Osama Ibrahim Alwassil,1 Sree Harsha,1 Koleka Mlisana4 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 Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal, India; 4Department of Microbiology, National Health Laboratory Services, KZN Academic Complex, Inkosi Albert Luthuli Central Hospital, Durban, South Africa Abstract: The novel (1-(4-aryl)-1H-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives were synthesized by the click reaction of the dihydropyrimidinones, bearing a terminal alkynyl group, with various substituted aryl azides at room temperature using a catalytic amount of Cu(OAc)2 and sodium ascorbate in a 1:2 ratio of acetone and water as a solvent. The newly synthesized compounds were characterized by a number of spectroscopic techniques, such as infrared, liquid chromatography-mass spectrometry, 1H, and 13C nuclear magnetic resonance along with single crystal X-ray diffraction. The current procedure for the synthesis of 1,2,3-triazole hybrids with dihydropyrimidinones is appropriate for the synthesis of a library of analogs 7a-l and the method accessible here is operationally simple and has excellent yields. The title compounds 7a-l were evaluated for their in vitro antitubercular activity against H37RV and multidrug-resistant strains of Mycobacterium tuberculosis by resazurin microplate assay plate method and it was found that compound 7d was promising against H37RV and multidrug-resistant strains of M. tuberculosis at 10 and 15 µg/mL, respectively. Keywords: 1,2,3-triazole, dihydropyrimidinone, click chemistry, antitubercular drug discovery, synthesi