oxadiazoles and Dengue

Zika virus (ZIKV), an arbovirus of the Flaviviridae family, has emerged as a significant public health concern owing to its association with congenital abnormalities and severe neurological sequelae. Thus, there is an urgent need to develop effective therapeutic approaches to efficiently treat ZIKV infections. This study used phenotypic screening to identify a series of 1,2,4-oxadiazole derivatives that possess antiviral activity against ZIKV infection. Subsequently, 28 new derivatives were designed, synthesized, and evaluated for this purpose. Among these compounds, 4-(5-phenyl-1,2,4-oxadiazol-3-yl)-N-(pyridin-3-ylmethyl)aniline (5d) had potent antiviral activity against ZIKV infections. Furthermore, a structure-activity relationship analysis indicated that a benzyl substitution on the aniline nitrogen of this compound improved potency while augmenting its drug-like properties. In addition, 5d exhibited antiviral activity against various viruses of Flaviviridae family of worldwide public health importance, such as dengue, Japanese encephalitis and classical swine fever viruses, indicating its potential as a lead compound for generating 1,2,4-oxadiazole derivatives with broad-spectrum anti-flaviviral properties.

Topics: Aniline Compounds; Antiviral Agents; Classical Swine Fever Virus; Dengue; Encephalitis, Japanese; Humans; Oxadiazoles; Virus Replication; Zika Virus; Zika Virus Infection

Using a functional high-throughput screening (HTS) and subsequent SAR studies, we have discovered a novel series of non-nucleoside dengue viral polymerase inhibitors. We report the elaboration of SAR around hit compound 1 as well as the synthesis and antiviral evaluation of 3-phenyl-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,2,4-oxadiazole and 5-phenyl-2-[2-(2-thienyl)ethenyl]-1,3,4-oxadiazole analogues derived from a rapid and easily accessible chemical pathway. A large number of compounds prepared by this method were shown to possess in vitro activity against the polymerase of dengue virus. The most potent inhibitors were tested against Dengue virus clinical isolates on infected cells model and exhibit submicromolar activity on the four dengue virus serotypes.

Topics: Animals; Antiviral Agents; Cell Line; Dengue; Dengue Virus; Humans; Oxadiazoles; RNA-Dependent RNA Polymerase; Thiophenes; Viral Nonstructural Proteins

1,2-Benzisothiazol-3(2H)-ones and 1,3,4-oxadiazoles individually have recently attracted considerable interest in drug discovery, including as antibacterial and antifungal agents. In this study, a series of functionalized 1,2-benzisothiazol-3(2H)-one-1,3,4-oxadiazole hybrid derivatives were synthesized and subsequently screened against Dengue and West Nile virus proteases. Ten out of twenty-four compounds showed greater than 50% inhibition against DENV2 and WNV proteases ([I] = 10 μM). The IC(50) values of compound 7n against DENV2 and WNV NS2B/NS3 were found to be 3.75 ± 0.06 and 4.22 ± 0.07 μM, respectively. The kinetics data support a competitive mode of inhibition by compound 7n. Molecular modeling studies were performed to delineate the putative binding mode of this series of compounds. This study reveals that the hybrid series arising from the linking of the two scaffolds provides a suitable platform for conducting a hit-to-lead optimization campaign via iterative structure-activity relationship studies, in vitro screening and X-ray crystallography.

Topics: Animals; Antiviral Agents; Dengue; Dengue Virus; Drug Design; Humans; Models, Molecular; Oxadiazoles; Peptide Hydrolases; Protease Inhibitors; Triazoles; West Nile Fever; West Nile virus