Due to the unavailability specific drugs or vaccines (FDA approved) that can cure COVID-19, the development of potent antiviral drug candidates/therapeutic molecules against COVID-19 is urgently required. This study was aimed at in silico screening and study of polyphenolic phytochemical compounds in a rational way by virtual screening, molecular docking and molecular dynamics studies against SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) enzymes. The objective of the study was to identify plant-derived polyphenolic compounds and/or flavonoid molecules as possible antiviral agents with protease inhibitory potential against SARS-CoV-2. In this study, we report plant-derived polyphenolic compounds (including flavonoids) as novel protease inhibitors against SARS-CoV-2. From virtual docking and molecular docking study, 31 polyphenolic compounds were identified as active antiviral molecules possessing well-defined binding affinity with acceptable ADMET, toxicity and lead-like or drug-like properties. Six polyphenolic compounds, namely, enterodiol, taxifolin, eriodictyol, leucopelargonidin, morin and myricetin were found to exhibit remarkable binding affinities against the proteases with taxifolin and morin exhibiting the highest binding affinity toward Mpro and PLpro respectively. Molecular dynamics simulation studies of these compounds in complex with the proteases showed that the binding of the compounds is characterized by structural perturbations of the proteases suggesting their antiviral activities. These compounds can therefore be investigated further by in vivo and in vitro techniques to assess their potential efficacy against SARS-CoV-2 and thus serve as the starting point for the development of potent antiviral agents against the deadly COVID-19. Communicated by Ramaswamy H. Sarma

The inhibition of D-alanine-D-alanine ligase (Ddl) prevents bacterial growth, which makes this enzyme an attractive and viable target in the urgent search for novel effective antimicrobial drugs. In this work, a series of novel coumarin-linked pyrazoline inhibitors of D-alanine-D-alanine ligase were synthesized and evaluated as inhibitors of Escherichia coli DdlB ligase in order to target resistant strains of bacteria using environmentally benevolent β-cyclodextrin as a supramolecular catalyst via one-pot four component synthesis in water as a green reaction media. All the newly synthesized compounds have been characterized by elemental analysis and various spectroscopic methods. The new procedure has noteworthy advantages including easy work-up, short reaction times, high yields of products and column-free synthesis. The synthesized compounds were evaluated in vitro for their antimicrobial activity. Among the synthesized compounds, namely 3-(5-(4-hydroxy-3-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one (5f) was found to be the most potent D-alanine-D-alanine ligase enzyme inhibitor, with an IC₅₀ value 106 μM, and the compound 3-(5-(p-tolyl)-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one (5g) was found to be the second-most potent inhibitor of the DdlB enzyme, with an IC₅₀ value 111 μM against the standard D-cycloserine. In addition, SAR study provided evidence that the –OH, –CH₃ and –OCH₃ groups at the 4- and 3-position of the coumarins linked to the pyrazolines scaffold increased enzymatic inhibition, while the molecular docking study of most active compounds 5a, 5g, and 5j against DdlB enzyme of E. coli exhibited good binding properties. This work thus highlights the coumarin-linked pyrazoline motif as a very promising tool for the development of novel antimicrobial compounds acting through an interesting bactericidal mechanism of action.

The present method provides a wide scope and quick access to dihydropyrido[2,3-d:6,5-d′]dipyrimidinetetraone and pyrimido[4,5-d]pyrimidine derivatives in good to excellent isolated yields from a one-pot three-component reaction of aldehydes, barbituric acid and ammonium acetate/urea in DIPEAc at room temperature. Major advantages of the present methodology are: use of green solvent, short reaction time, catalyst free, compatibility with a wide range of substrates, ease of recovery, reusability of the reaction medium, and DIPEAc as an alternative solvent and catalyst. All the synthesized compounds (3a–k) and (4a–g) were evaluated for their in vitro anticancer and tyrosinase inhibitory activity. In vitro anticancer screening of the synthesized compounds was performed against MCF-7, HeLa and A-549 cancer cell lines and 3f, 3h and 3i showed good activity. The compounds 3a, 3c, 3f and 3i showed good in vitro anticancer activity against SK-MEL-2. The synthesized compounds were also tested on non-tumorigenic MCF-10A cell lines and were found to be selective towards their cancer cell lines. At the IC₅₀ concentration of compound 3f there were typical morphological changes such as cell wall deformation, cell detachment, cell shrinkage and a reduced number of viable cells in MCF-7 cancer cell lines in comparison to control cells. Among the series, compounds 3f, 3h and 3i excellently inhibited the tyrosinase enzyme. A molecular docking study of the compounds was also performed and compounds showed overall very effective binding modes and good agglomeration in the active site by forming various interactions with active site residues. The in silico ADMET properties of the synthesized compounds showed that they possess worthy oral drug like properties.

Herein, we report an environmentally friendly, rapid, and convenient one-pot ultrasound-promoted synthesis of 5-amino-2-(4-chlorophenyl)-7-substituted phenyl-8,8a-dihydro-7H-(1,3,4)thiadiazolo(3,2-α)pyrimidine-6-carbonitrile derivatives. The in-vitro anticancer activities of these compounds were evaluated against four human tumor cell lines. Among all the synthesized derivatives, compound 4i, which has substituent 3-hydroxy-4-methoxyphenyl is found to have the highest GI₅₀ value of 32.7 μM, 55.3 μM, 34.3 μM, 28.9 μM for MCF-7, K562, HeLa and PC-3 cancer cell lines respectively. A docking study of the newly synthesized compounds were performed, and the results showed good binding mode in the active site of thymidylate synthase enzyme. ADME properties of synthesized compounds were also studied and showed good drug like properties.

Third generation EGFR inhibitor osimertinib was approved as the first-line treatment for EGFR T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC) patients in 2017. However, EGFR tertiary Cys797 to Ser797 (C797S) point mutation emanate rapidly after treatment of osimertinib, which is undruggable mutation to the all existing drugs. In this work, we have reported the novel T790M/C797S-EGFR Tyrosine Kinase inhibitors using BREED based de novo hybridization approach. BREED generates novel inhibitors from structures of known ligands bound to a common target. Among the generated hybridised breed compounds, the top best scorer breed molecules were breed 436, breed 530, breed 450, breed 562 and breed 313. Molecular Dynamics simulation of breed 436 for 10 ns further suggested that docked compound was stable into the pocket of the T790M/C797S-EGFR Tyrosine Kinase. In silico pharmacokinetic predictions of the breed hybridised compounds were within the defined range described for human use.