Rationally designed TNF-α inhibitors: Identification of promising cytotoxic agents.

Design and synthesis of new indole derivatives as tumor growth inhibiting agents via inhibiting the TNF-α is described. The preliminary results showed the inhibition of LPS induced production of NO, TNF-α and IL-6 by these compounds out of which compounds 2d and 2g exhibited appreciable cytotoxicity against the 60 cell lines panel of human cancer. The rationale behind the design of the molecules and the results of their biological studies are presented. 2009 Elsevier Ltd. All rights reserved.

Recent advances in the discovery of potent RNA-dependent RNA-polymerase (RdRp) inhibitors targeting viruses.

WHO has declared COVID-19 a pandemic, which has affected the whole world and has caused unprecedented social and economic disruption. Since the emergence of the disease, several druggable targets have been suggested including 3-chymotrypsin-like protease (3CLpro), spike, RNA-dependent RNA polymerase (RdRp), and the papain-like protease (PLpro) computational approach. From the beginning, viral replication has been the main focus for any antiviral drug development for viral diseases, including HCV, influenza virus, zika virus, norovirus, measles, dengue virus, and coronaviruses. This review lists the nucleoside, nucleotide, and non-nucleoside RdRp inhibitor analogues of various viral diseases that may be evaluated for drug development to treat COVID-19.

Rational modification of a lead molecule: Improving the antifungal activity of indole - triazole - amino acid conjugates.

The modification of a molecule that was identified as highly efficacious in the previous studies could considerably improve the biological activity of the resulting compounds. While targeting lanosterol 14-α demethylase, the molecular modelling studies convinced that the extension of the phenyl ring of compound 1 deep into the hydrophobic pocket of the enzyme may increase the enzyme - ligand interactions and hence improve the anti-fungal profile of the molecules. As a result, the newly designed compounds 2 were synthesized and screened for their anti-microbial properties and these compounds were found to exhibit considerably better activity than the previous molecule 1. Some of the compounds in this series exhibited MIC90 16 µg mL-1 and 32 µg mL-1 against Candida albicans and Aspergillus niger, respectively as against 312 µg mL-1 for compound 1.

Hybrid molecules: The privileged scaffolds for various pharmaceuticals.

The practice of polypharmacology is not a new concept but the approaches which are being adopted for administering the two or more drugs together are varied from time to time. Taking two or more drugs simultaneously, co-formulation of two or more active agents in a single tablet and development of hybrid molecular entities capable to modulate multiple targets are the three popular approaches for multidrug therapy. The simultaneous use of more than one drug for the chemotherapy of a single disease demands a lot of patient compliance. Hence the present form of polypharmacology is gaining popularity in the form of hybrid molecules (multiple ligand approach). From the last 1-2 decades, the synthesis of hybrid molecules by the combination of different biologically relevant moieties has been under constant escalation along with their evaluation as diverse range of pharmacological agents and as potent drugs. This review is focused on the biological potential of hybrid molecules with particular mention of those exhibiting anti-fungal, anti-tuberculosis, anti-malarial, anti-inflammatory and anti-cancer activities. A comparison of the drug potency of the hybrid molecules with their individual counterparts is discussed for quantifying the significance of the concept of molecular hybridisation.