AI Promoted Virtual Screening, Structure-Based Hit Optimization, and Synthesis of Novel COVID-19 S-RBD Domain Inhibitors.

Coronavirus disease 2019 (COVID-19) is caused by a new, highly pathogenic severe-acute-respiratory syndrome coronavirus 2 (SARS-CoV-2) that infects human cells through its transmembrane spike (S) glycoprotein. The receptor-binding domain (RBD) of the S protein interacts with the angiotensin-converting enzyme II (ACE2) receptor of the host cells. Therefore, pharmacological targeting of this interaction might prevent infection or spread of the virus.

Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors.

In today’s global plan to completely eradicate hepatitis C virus (HCV), the essential list of medications used for HCV treatment are direct-acting antivirals (DAAs), as interferon-sparing regimens have become the standard-of-care (SOC) treatment. HCV nonstructural protein 5A (NS5A) inhibitors are a very common component of these regimens. Food and Drug Administration (FDA)-approved NS5A inhibitors, although very potent, do not have the same potency against all eight genotypes of HCV.

Redesigning of the cap conformation and symmetry of the diphenylethyne core to yield highly potent pan-genotypic NS5A inhibitors with high potency and high resistance barrier.

Herein, we report the discovery of several NS5A inhibitors with potency against HCV genotype 1b in the picomolar range. Compounds (15, 33) were of extremely high potency against HCV genotype 1b (EC ≈ 1 pM), improved activity against genotype 3a (GT 3a) and good metabolic stability. We studied the impact of changing the cap conformation relative to the diphenylethyne core and/or compound symmetry on both potency and metabolic stability.

Examining barbiturate scaffold for the synthesis of new agents with biological interest.

Barbiturates have a long history of being used as drugs presenting wide varieties of biological activities (antimicrobial, anti-urease and antioxidant). Reactive oxygen species are associated with inflammation implicated in cancer, atherosclerosis and autoimmune diseases. Multitarget agents represent a powerful approach to the therapy of complicated inflammatory diseases.

Probing the Inhibition of Microtubule Affinity Regulating Kinase 4 by N-Substituted Acridones.

Microtubule affinity regulating kinase 4 (MARK4) becomes a unique anti-cancer drug target as its overexpression is responsible for different types of cancers. In quest of novel, effective MARK4 inhibitors, some acridone derivatives were synthesized, characterized and evaluated for inhibitory activity against human MARK4. Among all the synthesized compounds, three (7b, 7d and 7f) were found to have better binding affinity and enzyme inhibition activity in µM range as shown by fluorescence binding, ITC and kinase assays.