NMI-SO2Cl2-Mediated Amide Bond Formation: Facile Synthesis of Some Dihydrotriazolopyrimidine Amide Derivatives as Potential Anti-Inflammatory and Anti-Tubercular Agents.

Facile access to some novel biologically relevant dihydrotriazolopyrimidine carboxylic acid-derived amide analogues using NMI/SO2Cl2, and aromatic and aliphatic primary and secondary amines, is reported herein. The role of N-methylimidazole (NMI) as the base and sulfuryl chloride (SO2Cl2) as the coupling reagent has been effectively realized in accessing these molecules in good to excellent yields. The feasibility of the developed protocol has also been extended to the gram-scale synthesis of N-benzylbenzamide in a 75% yield from benzoic acid and benzyl amine. The newly synthesized compounds were tested via in vitro anti-inflammatory and anti-tubercular activity studies. The compounds 6aa and 6be were found to be the most active anti-inflammatory agents, whereas 6cb and 6ch were found to exhibit promising anti-tubercular potency when compared to other synthesized molecules. The structure-activity relationship (SAR) studies revealed the importance of the presence of electron-donating functionalities in enhancing the anti-inflammatory potential of the newly synthesized molecules. However, the presence of electron-withdrawing substituents was found to be significant for improving their anti-tubercular potency.

Sub-pocket-focused designing of tacrine derivatives as potential acetylcholinesterase inhibitors.

Human acetylcholinesterase (hAChE) has a potential role in the management of acetylcholine, one of the neurotransmitters that modulate the overall activity of cholinergic system, AChE inhibitors have a greater impact in the therapeutics. Though the atomic structure of hAChE has been extensively studied, the precise active site geometry upon binding to different ligands are yet to be explored. In the present study, an extensive structural analysis of our recently reported hAChE-tacrine complex has carried out and revealed the presence of two prominent sub-pockets located at the vicinity of the hAChE active site. Structural bioinformatics assisted studies designed 132 putative sub-pockets focused tacrine derivatives (SPFTDs), their molecular docking, free energy estimations revealed that they are stronger than tacrine in terms of binding affinity. Our in vitro studies also supported the in silico findings, all these SPFTDs are having better potencies than tacrine. Cytotoxic nature of these SPFTDs on HepG2 and Neuro-2a cell lines, diminishes the possibilities for future in vivo studies. However, the identification of these sub pockets and the SPFTDs paved a new way to the future drug discovery especially since AChE is one of the promising and approved drug targets in treatment of AD drug discovery.

Synthesis of trans N-Substituted Pyrrolidine Derivatives Bearing 1,2,4- triazole Ring.

BACKGROUND: 1,2,4-triazoles scaffolds display significant biological activities due to hydrogen bonding, solubility, dipole character, and rigidity. OBJECTIVE: The core motif of 1,2,4-triazoles plays a vital role in clinical drugs such as Rizatriptan (antimigraine), Ribavirin (antiviral), anastrozole (anticancer), etizolam (anxiolytic), estazolam (anticonvulsant), alprazolam (anti-hypnotic), letrozole (aromatase inhibitor), loreclezole (anticonvulsant), trazadone (antidepressant) etc. Methods: Epoxide ring opening of tert-butyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate followed by methylation under basic conditions and de-protection gave the corresponding trans 1-(4- methoxypyrrolidin-3-yl)-1H-1,2,4-triazole hydrochloride salt as the precursor. This precursor on reaction with substituted benzoyl chlorides and benzyl bromides gave the desired amide and amine products. RESULTS: A library of 14 N-substituted pyrrolidine derivatives i.e. trans3-methoxy-4-(1H-1,2,4-triazol- 1-yl) pyrrolidin-1-yl) (phenyl)methanone and trans 1-benzyl-4-methoxypyrrolidin-3-yl)-1H-1,2,4- triazole were prepared. CONCLUSION: Eight novel amides (6a-h) and six amines (8a-f) derivatives were synthesized using 1-(4- methoxypyrrolidin-3-yl)-1H-1,2,4-triazole 4 salt with substituted benzoyl chlorides and benzyl bromides.

Drug Re-purposing Approach and Potential Therapeutic Strategies to Treat COVID-19.

The current pandemic of COVID-19 caused by SARS-Cov-2 has posed a severe threat to the whole world with its highly infectious, progressive nature with up to 10% mortality rates. The severity of the situation faced by the whole world and the lack of efficient therapeutics to treat this viral disease have led the WHO to depend on the drug-repurposing approach to tackle this major global health problem. This review aims at highlighting the various synthetic approaches employed for the synthesis of these FDA approved drugs that have been presently used for COVID-19 treatment. Additionally, a brief overview of several therapeutic strategies is also presented. This review will encourage the scientific community across the globe to come up with better and efficient synthetic protocols and also novel chemical entities along with this core with more potent activity.

2-Aminoaryl-3,5-diaryl pyrazines: Synthesis, biological evaluation against Mycobacterium tuberculosis and docking studies.

Rationally designed Mycobacterium tuberculosis (Mtb) inhibitors were synthesized under Buchwald conditions using Pd2 (dba)3 /xantphos and the compounds were investigated for their biological activity against the Mtb standard strain H37Rv and two other clinically isolated multidrug-resistant strains with different drug resistance patterns. Compounds 5e, 6e, 7e, and 8e exhibited excellent antituberculosis activity against H37Rv with a minimum inhibitory concentration (MIC) value of 15 µg/ml. Compounds 5a, 6c, 7b, 8a, 8b, and 8d also displayed their potency with a MIC value in the range of 15-25 µg/ml. In addition to the Mtb studies, compounds 4e, 5e, 7e, and 8e were tested for cytotoxicity on HEK-293 cells and compounds 7e and 8e were identified to have low toxicities of up to 200 and 300 µM, respectively. The synthesized compounds docked with the 2FUM protein of Mtb and the docking studies revealed that compounds 5e, 6e, 7e, and 8e can bind strongly in the active site of the enzyme and showed binding energies of -9.62, -10.7, -11.48, and -12.06 kcal/mol, respectively. Compound 7e forms four hydrogen bonds, whereas compound 8e forms five hydrogen bonds with amino acids, respectively. Based on these results, compounds 7e and 8e might be considered potential lead compounds with good anti-Mtb potency.

A highly efficient precatalytic system (XPhos-PdG2) for the Suzuki-Miyaura cross-coupling of 7-chloro-1H-pyrrolo[2,3-c]pyridine employing low catalyst loading.

An expedient catalytic method for the synthesis of diverse 7-(hetero) aryl-1H-pyrrolo[2,3-c]pyridine analogues via microwave-assisted Suzuki-Miyaura cross-coupling reaction with excellent yield was developed. The method is found to be compatible with various boronic acids and potassium organotrifluoroborates. The formation of highly stable monoligated catalytic species is found to be instrumental in driving the reactions to excellent conversions in Suzuki-Miyaura coupling. Herein, we report our findings on the use of a highly efficient precatalytic system (XPhos-PdG2), containing a bulky monodentate biaryl ligand which allows the rapid reductive elimination to form the true monoligated Pd(0) catalytic species, thereby facilitating the Suzuki coupling reaction of 7-chloro, 6-azaindole system containing unprotected free N-H group with excellent conversions employing low catalyst loadings. Also, we observed that the use of near stoichiometric potassium organotrifluoroborate reagents as alternative coupling partners for boronic acids, which are prone to protodeboronation, resulted in excellent conversions.

Novel tacrine derivatives exhibiting improved acetylcholinesterase inhibition: Design, synthesis and biological evaluation.

A novel series of twenty four tacrine derivatives were designed and synthesised. Among these, thirteen were taken for the acetylcholinesterase (AChE) inhibition studies. Three compounds such as 4c, 6c and 6f were found to possess significant AChE inhibitory properties with IC50 values 12.97 ± 0.47 nM, 5.17 ± 0.24 nM and 7.14 ± 0.78 nM respectively. In silico docking studies revealed that these compounds can bind strongly in the active site of the enzyme and prevent enzyme-substrate interactions. On binding, the substituted groups were oriented either towards the peripheral anionic site (PAS) (Pocket A) or towards a hydrophobic cavity (pocket B) located near the active site. The cytotoxicity and hepatotoxicity of the compounds were tested using HEK-293 and HepG2 cell lines respectively. The compound 4c did not show any significant decrease in the cell viability even at a concentration of 300 µM indicating that its cytotoxicity and hepatotoxicity are significantly lesser compared to tacrine, due to the chemical modification. Based on the available results, it can be suggested that the compound 4c might be a potential drug lead compound with AChE inhibitory activity. However, further pharmacokinetic studies are necessary to comment on the efficacy of the compound as a drug for AD.