Novel fluorinated pyrazolo[1,5-a]pyrimidines: In a way from synthesis and docking studies to biological evaluation.

• A new fluorinated pyrazole[1,5- a ]pyrimidine derivatives were synthetized. • The structure of the designed compounds was confirmed by spectroscopic techniques. • Anti-viral and SAR study were evaluated and discussed. • The HVC protease were determined for the most promising compounds. • Docking study and ADMA were carried out as well as some physicochemical properties. 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 B 4 (COX-B 4), 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 IC 50 of 7.33 ± 0.51 μg/ml, compared to IC 50 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. [Display omitted] [ABSTRACT FROM AUTHOR]