Synthesis, Antiviral and Kinesin Eg5 Activities of New Indomethacin Analogues

Aim: Synthesis, characterization, anti-HIV, anti-HCV and kinesin activities of new indomethacin analogues have been carried out.

Methodology: Arylated derivatives of indomethacin via the Suzuki-Miyaura cross-coupling reaction using palladium acetate/triphenylphophineor palladium based N-heterocyclic carbene (Pd-NHC) complexe as catalysts were synthesized and characterized by the 1H and 13C and 2D NMR study. Analogously, indomethacin analogues bearing thioureido and amide moieties of various L-amino acid esters were prepared via Kabbani and coupling reactions, respectively.

Results: All the new analogues were evaluated In vitro for their antiviral activity against the replication of HIV-1 and HIV-2 in MT-4 cells using MTT assay. Compounds 28, 31 and 32 were evaluated In vitro for their inhibitory activity against hepatitis virus C (HCV) in the Huh 5-2 replicon system (type 1b, Con1 strain). Additionally, some analogues were screened for their inhibitory activity against the ATPase enzyme and the motor-protein Kinesin Eg5.In conclusion, Compounds 31 and 39 showed anti-HIV activity with IC50 values of >1.81 and > 3.21μM (CC50 of 3.31 and 28.89μM), resulting in selectivity indexs (SI) of 6 and 9, respectively.

Conclusion: Compounds 31 and 39 displayed better anti-HIV activity than the other derivatives (SI = 6 and 9, respectively). Compound 27 showed ATPase inhibition value of 48% at 100 µM concentration.