Investigating the antiviral therapeutic potentialities of marine polycyclic lamellarin pyrrole alkaloids as promising inhibitors for SARS-CoV-2 and Zika main proteases (Mpro).

The new coronavirus variant (SARS-CoV-2) and Zika virus are two world-wide health pandemics. Along history, natural products-based drugs have always crucially recognized as a main source of valuable medications. Considering the SARS-CoV-2 and Zika main proteases (Mpro) as the re-production key element of the viral cycle and its main target, herein we report an intensive computer-aided virtual screening for a focused list of 39 marine lamellarins pyrrole alkaloids, against SARS-CoV-2 and Zika main proteases (Mpro) using a set of combined modern computational methodologies including molecular docking (MDock), molecule dynamic simulations (MDS) and structure-activity relationships (SARs) as well. Indeed, the molecular docking studies had revealed four promising marine alkaloids including [lamellarin H (14)/K (17)] and [lamellarin S (26)/Z (39)], according to their notable ligand-protein energy scores and relevant binding affinities with the SARS-CoV-2 and Zika (Mpro) pocket residues, respectively. Consequentially, these four chemical hits were further examined thermodynamically though investigating their MD simulations at 100 ns, where they showed prominent stability within the accommodated (Mpro) pockets. Moreover, in-deep SARs studies suggested the crucial roles of the rigid fused polycyclic ring system, particularly aromatic A- and F- rings, position of the phenolic -OH and δ-lactone functionalities as essential structural and pharmacophoric features. Finally, these four promising lamellarins alkaloids were investigated for their in-silico ADME using the SWISS ADME platform, where they displayed appropriated drug-likeness properties. Such motivating outcomes are greatly recommending further in vitro/vivo examinations regarding those lamellarins pyrrole alkaloids (LPAs).Communicated by Ramaswamy H. Sarma.

Design and synthesis of naturally-inspired SARS-CoV-2 inhibitors.

A naturally inspired chemical library of 25 molecules was synthesised guided by 3-D dimensionality and natural product likeness factors to explore a new chemical space. The synthesised chemical library, consisting of fused-bridged dodecahydro-2a,6-epoxyazepino[3,4,5-c,d]indole skeletons, followed lead likeness factors in terms of molecular weight, C-sp3 fraction and Clog P. Screening of the 25 compounds against lung cells infected with SARS-CoV-2 led to the identification of 2 hits. Although the chemical library showed cytotoxicity, the two hits (3b, 9e) showed the highest antiviral activity (EC50 values of 3.7 and 1.4 µM, respectively) with an acceptable cytotoxicity difference. Computational analysis based on docking and molecular dynamics simulations against main protein targets in SARS-CoV-2 (main protease Mpro, nucleocapsid phosphoprotein, non-structural protein nsp10-nsp16 complex and RBD/ACE2 complex) were performed. The computational analysis proposed the possible binding targets to be either Mpro or the nsp10-nsp16 complex. Biological assays were performed to confirm this proposition. A cell-based assay for Mpro protease activity using a reverse-nanoluciferase (Rev-Nluc) reporter confirmed that 3b targets Mpro. These results open the way towards further hit-to-lead optimisations.

Discovery of New 1,3,4-Oxadiazoles with Dual Activity Targeting the Cholinergic Pathway as Effective Anti-Alzheimer Agents.

Finding an effective anti-Alzheimer agent is quite challenging due to its multifactorial nature. As such, multitarget directed ligands (MTDLs) could be a promising paradigm for finding potential therapeutically effective new small-molecule bioactive agents against Alzheimer's disease (AD). We herein present the design, synthesis, and biological evaluation of a new series of compounds based on a 5-pyrid-3-yl-1,3,4-oxadiazole scaffold. Our synthesized compounds displayed excellent in vitro enzyme inhibitory activity at nanomolar (nM) concentrations against two major AD disease-modifying targets, i.e., acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among our compounds, 5e was considered the best dual inhibitor of both AChE (IC50 = 50.87 nM) and BuChE (IC50 = 4.77 nM), where these values surpassed those of rivastagmine (the only FDA-approved dual AChE and BuChE inhibitor) in our study. Furthermore, in vivo and ex vivo testing of the hit compound 5e highlighted its significant AD-biotargeting effects including reducing the elevated levels of lipid peroxidation and glutathione (GSH), normalizing levels of 8-OHdG, and, most importantly, decreasing the levels of the well-known AD hallmark ß-amyloid protein. Finally, the binding ability of 5e to each of our targets, AChE and BuChE, was confirmed through additional molecular docking and molecular dynamics (MD) simulations that reflected good interactions of 5e to the active site of both targets. Hence, we herein present a series of new 1,3,4-oxadiazoles that are promising leads for the development of dual-acting AChE and BuChE inhibitors for the management of AD.