Design and Synthesis of Highly Active Antimycobacterial Mutual Esters of 2-(2-Isonicotinoylhydrazineylidene)propanoic Acid

The combination of two active scaffolds into one molecule represents a proven approach in drug design to overcome microbial drug resistance. We designed and synthesized more lipophilic esters of 2-(2-isonicotinoylhydrazineylidene)propanoic acid, obtained from antitubercular drug isoniazid, with various alcohols, phenols and thiols, including several drugs, using carbodiimide-mediated coupling. Nineteen new esters were evaluated as potential antimycobacterial agents against drug-sensitive Mycobacterium tuberculosis (Mtb.) H37Rv, Mycobacterium avium and Mycobacterium kansasii. Selected derivatives were also tested for inhibition of multidrug-resistant (MDR) Mtb., and their mechanism of action was investigated. The esters exhibited high activity against Mtb. (minimum inhibitory concentrations, MIC, from ≤0.125 μM), M. kansasii, M. avium as well as MDR strains (MIC from 0.25, 32 and 8 µM, respectively). The most active mutual derivatives were derived from 4-chloro/phenoxy-phenols, triclosan, quinolin-8-ol, naphthols and terpene alcohols. The experiments identified enoyl-acyl carrier protein reductase (InhA), and thus mycobacterial cell wall biosynthesis, as the main target of the molecules that are activated by KatG, but for some compounds can also be expected adjunctive mechanism(s). Generally, the mutual esters have also avoided cytotoxicity and are promising hits for the discovery of antimycobacterial drugs with improved properties compared to parent isoniazid.

Computational Prediction of HCV RNA Polymerase Inhibitors from Alkaloid Library

Hepatitis C virus (HCV) is a global challenge and the leading cause of chronic liver disease. Approximately 30% of a patient infected with chronic HCV results into liver cirrhosis. WHO reports that 3% of the world’s population has been infected with HCV, which signifies that about 170 million people are at risk of developing chronic liver diseases globally. Research has shown that HCV NS5B polymerase is one of the six non-structural proteins encoded in the approximately 9600 nucleotide genome of HCV, which plays a vital role in the replication and infection of HCV virus; therefore, it serves as a target enzyme for antiviral therapy against HCV. In this study, Alkaloids, a group of vital secondary metabolites in plants, with cyclic structures containing nitrogen in a negative oxidation state which is limitedly distributed in a living organism, were mined from an online database and screened computationally using a molecular docking approach to predict its inhibitory potential against the replication of HCV’s viral RNA. 259 Alkaloids was retrieved and docked, and it resulted that 3-(4-methoxyphenyl)-3-[[2-(4-methoxyphenyl)-1-oxoethyl]amino]propanoic acid, 14-norpseurotin A, and (+)-aplysinilin are predicted to be suitable inhibitors against NS5B through their binding pose and interactions with the amino acid residues at the binding site of NS5B. Additionally, hit compounds from the docking result were further subjected to ADME/Tox screening to predict their drug-likeness characteristics, and 3-(4-methoxyphenyl)-3-[[2-(4-methoxyphenyl)-1-oxoethyl]amino]propanoic acid stands out by showing more drug-like characteristics.

Hybrids of Thiazolidin-4-Ones and 1,3,4-Thiadiazole: Synthesis and Biological Screening of A Potential New Class of Acetylcholinesterae Inhibitors

Using propanoic acid and thiosemicarbazide as starting materials, a new sequence of thiazolidin-4-one analogs with thiadiazole derivative was synthesized in appreciable yield. Spectral techniques such as IR, 1H NMR, 13C NMR, and MS were used to validate the structures of the synthesized compounds (4a-t). In vitro acetylcholinesterase inhibitory activity of these synthesized compounds was assessed using an Ellman's method spectrophotometer and donepezil as a standard drug. Compounds 2-((5-ethyl-1,3,4-thiadiazol-2-yl)imino)-5-(4-methylbenzylidene)thiazolidin-4-one(4o) and 5-(4-(benzyloxy)benzylidene)-2-((5-ethyl-1,3,4-thiadiazol-2-yl)imino)thiazolidin-4-one(4i) were found to be potent AChE enzyme inhibitors, with pIC50 (mM) values of 1.30±0.007 and 1.22±0.002, respectively. Finally, these significant results could pave the way for the development of new AChE inhibitors and will serve as the basis for future research.