P33.08
Background: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) considered as structurally diverse group of compounds, act by inhibiting the reverse-transcriptase (RT) enzyme in an allosteric mode by binding to the polymerase active site causing a distortion of the catalytic aspartate triad in a non-competitive fashion. Consequently, a wide chemical opportunity exists, due to the flexibility of the NNRTI binding pocket (NNIBP) in the RT. In continuation of our ongoing efforts in the discovery of economic NNRTI agents, herein, we wish to report a novel class of pyrazoles and pyrimidines in order to obtain more effective candidates.
Methods: A novel series of pyrazole and pyrimidine compounds has been developed via cyclocondensation reaction. These molecules have been subsequently tested for anti-HIV activity using TZM-bl cell lines along with Luciferase expression profile of the TZM-bl cells after infecting with NL4.3 virus and MTT assay for the cytotoxicity determination.
Results: In Anti-HIV assay, molecules having pyrazole amine with distant position of electron withdrawing group showed 91–98 % inhibition. Further these compounds in Luciferase assay showed considerable inhibition of infection. While in cytotoxicity assay, it was observed that an increase in the concentration of most active compounds from 25 mg/mL to 125 mg/mL did not appreciably lower the percentage of cell viability. A close inspection of the best docked pose of most active compound clearly establish that it attained a “horseshoe-like” conformation and interaction with the Tyr181 and Tyr188 of the p66 subunit in the NNIBP.
Conclusions: As a concluding remark, we have developed a novel series of compounds with potent anti-HIV activity. It was confirmed that the designed molecules have the possibility of introducing chemical diversity around the core skeleton to generate new, potent molecules.
