Ultrasound assisted Cu-catalyzed Ullmann-Goldberg type coupling-cyclization in a single pot: Synthesis and evaluation of 11-pyrido[2,1-]quinazolin-11-ones against SARS-CoV-2 RdRp.

The evaluation of 11-pyrido[2,1-]quinazolin-11-one derivatives against SARS-CoV-2 RdRp was undertaken based on the reports on antiviral activities of this class of compounds in addition to the promising interactions of the antiviral drug penciclovir as well as quinazoline derivatives with SARS-CoV-2 RdRp . The target compounds were prepared an Ullmann-Goldberg type coupling followed by the subsequent cyclization (involving amidation) in a single pot. The methodology involved a CuI-catalyzed reaction of 2-iodobenzoate ester with 2-aminopyridine or quinolin-2-amine or thiazol-2-amine under ultrasound to give the expected products in acceptable (51-93%) yields. The molecular interactions of the synthesized 11-pyrido[2,1-]quinazolin-11-one derivatives with the SARS-CoV-2 RdRp (PDB: 7AAP) were evaluated . The study suggested that though none of these compounds showed interactions better than penciclovir but the compound and appeared to be comparable along with seemed to be nearly comparable to favipiravir and remdesivir. The compound with the best binding energy (-79.85 Kcal/mol) participated in the H-bond interactions through its OMe group with THR556 as well as ARG624 and the N-5 atom with the residue SER682. The studies further suggested that majority of the compounds interacted with the main cavity of active site pocket whereas and that showed relatively lower binding energies (-66.06 and -66.28 Kcal/mol) interacted with the shallow cavity underneath the active site of SARS CoV-2 RdRp. The study also revealed that a OMe group was favourable for interaction with respect to its position in the order C-8 > C-1 > C-2. Further, the presence of a fused quinoline ring was tolerated whereas a fused thiazole ring decreased the interaction significantly. The predictions of pharmacokinetic properties of and indicated that besides the BBB (Blood Brain Barrier) penetration potential these molecules may show a good overall ADME. Overall, the regioisomers and have emerged as molecules of possible interest in the context of targeting COVID-19.