Synthesis, characterized, QSAR studies and molecular docking of some phosphonates as COVID-19 inhibitors.

The global coronavirus (COVID-19) outbreak has prompted scientists to discover a cure for the disease. So far, phosphorus-based drugs have been proposed. These drugs have good inhibitory activity against the main protease (Mpro). Hence, in order to introduce a group of inhibitors the coronavirus, 51 compounds containing different mono, bis, and tetra phosphonates as Remdesivir derivatives, 32 of which are new, were synthesized and characterized by 31P, 13C, and 1H NMR and IR spectroscopy. Their biological activities were also investigated by Molecular Docking, QSAR, and Pharmacophore. Van der Waals, hydrogen bonding, and hydrophobic interactions were studied for all compounds as well as binding energy (△G, Kcal/mole) and the inhibitory constant Ki (µM) obtained by Molecular Docking. The results showed that the topology of the ligands and the change of the different groups attached to them can be effective in the placement position in the active site of the enzyme (Glu 166 and Gln 189). And bisphosphonates have a high interaction tendency with Mpro COVID-19. Compound L24 was identified as the best inhibitor with the -6.38 kcal/mol binding energy. The quantitative structure-activity relationship (QSAR) findings demonstrated that the polarity and topology of molecules in all phosphonate derivatives were important parameters affecting the effecting on the binding energy and inhibitory ability of compounds. The DFT and pharmacophore results are in good accordance with those of QSAR and molecular docking. This study can be helpful to gain a better understanding of the interactions between the Mpro of virus and its inhibitors in order to attain drugs with more effect on coronavirus (COVID-19).

Synthesis, crystal structure, cholinesterase inhibitory activity, evaluation of insecticidal activities, and computational studies of new phosphonic acids.

In an attempt to obtain the modified and novel insecticides with low human toxicity, a series of novel mono-, bis-, and tetraphosphonic acid derivatives were designed and characterized by infrared, 1H, 13C, and 31P NMR spectroscopy and X-ray crystallography. The inhibitory effects of the synthesized compounds were evaluated using the in vitro Ellman method on human and insect acetylcholinesterase (AChE). Some of these compounds, which had low human and high insect toxicity, were chosen to assess the killing effects (in vivo) on third larval instar of elm leaf beetle (X. luteola). In vivo and in vitro evidence has revealed that bisphosphonic acids, containing hydrophobic systems, have a good selectivity of insect AChE inhibition. In the present study, docking results showed that bisphosphonic acids had lower binding energy and higher inhibition compared with tetraphosphonic acids due to the type of their topology and the ability of their hydrogen to interact with the catalytic triad (the main active site of the enzyme). Additionally, the QSAR results demonstrated that the major effecting factors on the insecticidal activity of the subject compounds are the hydrophobicity, size, shape, and ability to form a hydrogen bond. The present study can be helpful in the development of new insecticides.

Evaluating anti-coronavirus activity of some phosphoramides and their influencing inhibitory factors using molecular docking, DFT, QSAR, and NCI-RDG studies.

The recent prevalence of coronavirus disease in 2019 (COVID-19) has triggered widespread global health concerns.Antiviral drugs based on phosphoramides have significant inhibitory activity against the main protease (Mpro) of the virus and prevent transcription and viral replication. Hence, in order to design and introduce a group of inhibitors affecting the coronavirus, 35 phosphoramide compounds based on phospho-guanine and phospho-pyrazine derivatives were selected for molecular docking study. The results showed that most phosphoguanides containing the amino benzimidazole have a high interaction tendency with COVID-19. Among them, compound 19 was identified as the strongest inhibitor with the -9.570 kcal/mol binding energy whereas, the binding energy of Remdesivir is -6.75 kcal/mol. The quantitative structure-activity relationship (QSAR) results demonstrated that the number of aromatic rings, amide's nitrogens and their ability in π-staking, and hydrogen interactions with Mpro active sites are major factors contributing to the inhibitory activity of these compounds.Also, the NCI-RDG and DFT results were in good accordance with those of QSAR and molecular docking. The findings of this investigation can be underlying the synthesis of effective and efficient drugs against COVID-19.

Gold-catalyzed domino cyclization-alkynylation reactions with EBX reagents: new insights into the reaction mechanism.

Gold-catalyzed domino processes constitute a useful alternative to C-H functionalization for the synthesis of functionalized (hetero)arenes. Herein, we report computational studies on the gold-catalyzed cyclization alkynylation of keto-allenes with ethynylbenziodoxole (EBX) reagents, which identified a gold(i) picolinate complex as the active catalyst, giving the first mechanistic insights into this transformation.