Recent Development in Small Molecules for SARS-CoV-2 and the Opportunity for Fragment-Based Drug Discovery.

The ongoing pandemic of Covid-19 caused by SARS-CoV-2 is a major threat to global public health, drawing attention to develop new therapeutics for treatment. Much research work is focused on identifying or repurposing new small molecules to serve as potential inhibitors by interacting with viral or host-cell molecular targets and understanding the nature of the virus in the host cells. Identifying small molecules as potent inhibitors at an early stage is advantageous in developing a molecule with higher potency and then finding a lead compound for the development of drug discovery. Small molecules can show their inhibition property by targeting either the SARS-CoV-2 main protease (Mpro) enzyme, papain-like protease (PLpro) enzyme, or helicase (Hel), or blocking the spike (S) protein angiotensin-converting enzyme 2 (ACE2) receptor. A very recent outbreak of a new variant (B.1.617.2-termed as Delta variant) of SARS-CoV-2 worldwide posed a greater challenge as it is resistant to clinically undergoing vaccine trials. Thus, the development of new drug molecules is of potential interest to combat SARS-CoV-2 disease, and for that, the fragment-based drug discovery (FBDD) approach could be one of the ways to bring out an effective solution. Two cysteine protease enzymes would be an attractive choice of target for fragment-based drug discovery to tune the molecular structure at an early stage with suitable functionality. In this short review, the recent development in small molecules as inhibitors against Covid-19 is discussed, and the opportunity for FBDD is envisioned optimistically to provide an outlook regarding Covid-19 that may pave the way in the direction of the Covid-19 drug development paradigm.

Iterative direct C(sp3)-H functionalization of amines: diastereoselective divergent syntheses of α,α'-disubstituted alicyclic amines.

A novel iterative C(sp3)-H oxygenation/C-C bond formation strategy, which avoids repetitive N-protection/-deprotection steps, was developed for direct α,α'-difunctionalization of alicyclic amines. The method is highly efficient and stereoselective in producing syn-α,α'-disubstituted aliphatic N-heterocycles. Synthetic potential and practicability of the method was demonstrated by an easy and straightforward synthesis of neuroactive alkaloid nor-lobelane and its derivatives.

Classical-Reaction-Driven Stereo- and Regioselective C(sp(3) )-H Functionalization of Aliphatic Amines.

A large variety of synthetic methods have been developed for the synthesis of functionalized aliphatic amines because of their broad spectrum of application. Metallic reagents/catalysts and/or toxic oxidants are involved in most of the cases. Direct CH functionalization of aliphatic amines via their classical condensation reactions with suitable carbonyl compounds is advantageous because this method avoids hazardous metallic reagents, toxic oxidants and pre-activation/pre-functionalization step(s). In this account, the concept of direct CH functionalization of aliphatic amines based on the classical condensation-isomerization-addition (CIA) strategy followed by recent contributions from our ongoing research in the field along with relevant examples from other groups are described. Successes in stereo- and regioselective CC and CO bond formation via direct α- as well as ß-C(sp(3) )-H functionalization are discussed.

Synthesis, In silico studies and In vitro evaluation for antioxidant and antibacterial properties of diarylmethylamines: A novel class of structurally simple and highly potent pharmacophore.

A series of novel diarylmethylamines were synthesized via simple three component condensation reaction. In vitro antibacterial activity of the synthesized compounds was assessed against Gram-positive and Gram-negative bacteria. Compound 1f containing phenyl and N-methyl piperazine moiety was found to be potent against both pathogenic bacteria with MIC value of 31µg/mL. Diarylmethylamine 1l containing sesamol and N-methyl piperazine units was found to be the most effective against Gram-positive bacteria with MIC value of 15µg/mL. The compound leads to the damage of the bacterial cell membrane which was demonstrated by flow cytometry (FC) and field emission scanning electron microscopy (FESEM). Radical scavenging activity of compounds 1l and 1m was found out to be comparable with that of standard antioxidant BHT. Further, in silico studies were carried out to calculate the physico-chemical parameter of the synthesized compounds.

Direct ß-C(sp(3))-H Functionalization of Aliphatic Amines to α,ß-Unsaturated Imines, Aldehydes, and Chromenes.

A metal-free method for direct ß-C(sp(3))-H functionalization of aliphatic amine was developed. The method is based on a reaction that yields enamine directly from the corresponding aliphatic amine, which otherwise requires the aid of metallic reagent and/or external oxidant. The reaction is operationally simple, general, and highly efficient in functionalizing both cyclic and acyclic amines. Structurally diverse unsaturated imines were obtained from N-heterocycles, while acyclic amines provided 2-alkyl cinnamaldehyde and benzopyran derivatives with excellent E/Z-selectivity.

Diastereoselective α-C-H functionalization of aliphatic N-heterocycles: an efficient route to ring fused oxazines.

A novel method for direct C-H functionalization of saturated N-heterocycles allowing easy access to synthetically as well as biologically important and structurally diverse ring-fused oxazines is developed. The method is operationally simple and highly diastereoselective. Moreover, it is efficient in functionalizing broad classes of both cyclic and acyclic amines including the substrates that are otherwise difficult to functionalize.