Novel pyrimidine-benzimidazole hybrids with antibacterial and antifungal properties and potential inhibition of SARS-CoV-2 main protease and spike glycoprotein

• Published in: Digital Chinese medicine (Online) Vol. 4; no. 2; pp. 102 - 119
• Main Authors: Khan, Sharuk, Kale, Mayura, Siddiqui, Falak, Nema, Nitin
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.06.2021
• Subjects: Antifungal; Bacteria; COVID-19; Molecular docking; Pyrimidine-benzimidazole; SARS-CoV-2 inhibitor; COVID-19; Pyrimidine-benzimidazole; Bacteria; SARS-CoV-2 inhibitor; Antifungal; Molecular docking
• ISSN: 2589-3777; 2589-3777
• DOI: 10.1016/j.dcmed.2021.06.004

The study aimed to synthesize and characterize pyrimidine-linked benzimidazole hybrids, define their antimicrobial and antifungal activities in vitro, and determine their ability to inhibit the main protease and spike glycoprotein of SARS-CoV-2. The ability of the synthesized compounds to inhibit the main protease and spike glycoprotein inhibitory of SARS-CoV-2 was investigated by assessing their mode of binding to the allosteric site of the enzyme using molecular docking. The structures of pyrimidine-linked benzimidazole derivatives synthesized with microwave assistance were confirmed by spectral analysis. Antibacterial and antifungal activities were determined by broth dilution. Gram-negative bateria (Escherichia coli and Pseudomonas aeruginosa) were more sensitive than gram-positive bateria (Staphylococcus aureus and Streptococcus pyogenes) to the derivatives. Candida albicans was sensitive to the derivatives at a minimal inhibitory concentration (MIC) of 250 μg/mL. The novel derivatives had better binding affinity (kcal/mol) than nelfinavir, lopinavir, ivermectin, remdesivir, and favipiravir, which are under investigation as treatment for SARS-CoV-2 infection. Compounds 2c, 2e, and 2g formed four hydrogen bonds with the active cavity of the main protease. Many derivatives had good binding affinity for the RBD of the of SARS-CoV-2 spike glycoprotein with the formation of up to four hydrogen bonds. We synthesized novel pyrimidine-linked benzi-midazole derivatives that were potent antimicrobial agents with ability to inhibit the SARS-CoV-2 spike glycoprotein. Understanding the pharmacophore features of the main protease and spike glycoprotein offers much scope for the development of more potent agents. We plan to optimize the properties of the derivatives using models in vivo and in vitro so that they will serve as more effective therapeutic options against bacterial and SARS-CoV-2 infections.