Abstract
Starting compound 2-cyanomethyl-7-(thiophen-2-yl)-5-trifluoromethylpyrazolo[1,5-a]pyrimidine-3-carbonitrile 3 reacts with aromatic aldehydes, aromatic diazonium salts, o-hydroxybenzaldehyde and isatin, a series of new fluorinated pyrazolo[1,5-a]pyrimidine derivatives were obtained. Additionally, the enamine derivative of compound 3 reacts with each of hydrazine hydrate and guanidine hydrochloride to form fluorinated ployheterocycles. The newly synthesized compounds were characterized by spectral data (IR, 1H NMR, 13C NMR and MS) and elemental analyses. Some selected compounds were tested in vitro for antiviral activity against Coxsackie virus B4(COX-B4), Rift Valley Fever (RVF), Vesicular stomatitis virus (VSV), and Encephalomyocarditis (EMCV) virus. The results of the antiviral evaluation of some new compounds 3, 5c, 5i, 7b, and 15 showed good antiviral activity against the tested viruses, for example compound 5c containing the withdrawing group (Cl) showed 26.6% inhibition against COX-B4, while 5i containing the furan moiety showed decreased activity compared to 5c (21%). Furthermore, compound 15 which is a fused compound showed an inhibitory effect 23%. Also, compounds 3, 5c, 5i, 7b and 15 were evaluated against the HCV-NS3 protease using Sovaldi as a control. The results showed that compound 5c had a good inhibitory effect on hepatitis C virus protease (HCV-NS3), with an IC50 of 7.33 ± 0.51 μg/ml, compared to IC50 of Sovaldi 3.20 ± 1.33 μg/ml. The virucidal activity of 5c was also determined by direct and indirect methods. The direct method showed moderate antiviral activity (0.76 log(10) / ml, corresponding to the percentage depletion of the virus infectivity titer of 13.8%. In contrast, the indirect method showed better antiviral activity, which was dependent on the time of application (1.75 log (10) /ml), which is 31.828%. Molecular Operating Environment software (MOE, 2015.10) was used to dock compounds 3, 5c, 15 compared to Sovaldi as a reference drug with the active site of co-crystallized B-Raf (PDB code: 3II5). The results showed good formation of hydrogen bonds between the functional groups NH, CO, CN, S atom and N atom of the target compounds with His 573, Thr 528, Cys 531, Glu 500, lle 591, Asp 593 and Gly 595 residues in terms of bond length and binding energy compared to Sovaldi. In addition, Absorption Metabolism Distribution Excretion studies (ADME) are used in the drug development process to study various factors that influence drug action and efficacy. Thus ADME was performed for compounds 3, 5c and 15 and showed that compound 3 could be absorbed through the gastrointestinal tract compared to other compounds tested.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.