Wang Resin Catalyzed Green Synthesis of 1,8-Dioxo-octahydroxanthene Derivatives and their in Silico/in vitro Evaluation against SIRT1

Because of important role in cancer, sirtuins especially the SIRT1 is viewed as an interesting pharma- cological target for developing potential anticancer agents. Based on our previous studies on sirtuin in- hibitory potential of 1,8-dioxodecahydroacridines we extended our efforts towards exploring the struc- turally relevant 1,8-dioxo-octahydroxanthene derivatives for the similar pharmacological evaluations. The targeted 1,8-dioxo-octahydroxanthenes were conveniently accessed via the sonochemical condensation of a range of (het)aryl aldehydes with 5,5-dimethyl-1,3-cyclohexanedione in water. All these reactions were catalyzed by the sulphonic acid-functionalized Wang resin (Wang-OSO3H) that was recovered and reused for several times without major loss of its catalytic efficiency. This eco-friendly approach afforded the desired products in good to high (87–96%) yields. Initial in silico docking of 1,8-dioxo-octahydroxanthene derivatives possessing a 6-membered aryl ring at the C-9 position into SIRT1 suggested inferior binding interactions in most of the cases (total estimated energy \u3c 82 kcal/mol). While two of these compounds e.g. 3a and 3l showed H-bond interactions through a carbonyl group with the residue ILE347 and ASP348 and a pi-sigma and pi-pi interaction with the residue PHE297 and PHE273 through a methyl group and the C-9 phenyl ring, respectively the size of the C-9 aryl ring seemed to have played a key role in the binding interactions of this class of compounds. Indeed, replacing the 6-membered aryl ring at C-9 by a 5-membered heteroaryl ring e.g. furan or thiophene afforded compounds that showed superior inter- actions (total estimated energy -98.18 and -89.9 kcal/mol) with SIRT1 in silico. The furan analogue 3q showed three H-bond interactions through its two carbonyl groups with the residues HIS363, ILE347 and ASP348 and a pi-pi interaction through the C-9 furan ring. The good in silico interactions of compound 3q were further supported by the initial in vitro assay when this compound showed encouraging inhibition (\u3e 87%) of SIRT1 at 10 μM. The in silico and in vitro studies identified compound 3q along with two other analogues for further pharmacological studies

Ultrasound Assisted Cu-catalyzed Ullmann-Goldberg Type Coupling-cyclization in a Single Pot: Synthesis and inSsilico Evaluation of 11H-pyrido[2,1-b]quinazolin-11-ones Against SARS-CoV-2 RdRp

The in silico evaluation of 11H-pyrido[2,1-b]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 in silico. The target compounds were prepared via 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 11H-pyrido[2,1-b]quinazolin-11-one derivatives with the SARS-CoV-2 RdRp (PDB: 7AAP) were evaluated in silico. The study suggested that though none of these compounds showed interactions better than penciclovir but the compound 3a and 3n appeared to be comparable along with 3b seemed to be nearly comparable to favipiravir and remdesivir. The compound 3n 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 via the N-5 atom with the residue SER682. The in silico studies further suggested that majority of the compounds interacted with the main cavity of active site pocket whereas 3h and 3o 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 \u3e C-1 \u3e C-2. Further, the presence of a fused quinoline ring was tolerated whereas a fused thiazole ring decreased the interaction significantly. The in silico predictions of pharmacokinetic properties of 3a, 3b and 3n indicated that besides the BBB (Blood Brain Barrier) penetration potential these molecules may show a good overall ADME. Overall, the regioisomers 3a, 3b and 3n have emerged as molecules of possible interest in the context of targeting COVID-19