Abstract
Objectives: New derivatives of 2-(1-(2-flouro-[1,1-biphenyl]-4-yl)ethyl)-6-(substituted phenyl) imidazole[2,1-b][1,3,4]thiadiazole, compounds(2-5), were designed and synthesized from the starting parent molecule, flurbiprofen.
Materials and Methods: Compound (1) was synthesized by refluxing flurbiprofen, as a starting material , with phosphorus oxychloride (POCl3), and thiosemicarbazide, resulting in flurbiprofen -1,3,4 thiadiazole -2 amine derivative. The target compounds(2-5) were obtained by refluxing compound(1) with different substituted phenacyl bromides,
Results: The new compounds were characterized by FTIR, 1HNMRs and CHNS analysis. A molecular docking study of the synthesized compounds (2-5) against HIV protease indicated such compounds occupied the critical site of HIV protease pocket, and demonstrated excellent positioning of the compounds in the pocket. The best binding energy values were (-7.49, -7.22 , -7.51 and-7.12 kcal/mol) for the compounds (2 -5(, respectively. The anticipated physio-chemical parameters(calculated logarithmic of partition cofficent(Clog p),molecular volume (MV), number of violations (nviol), topological surface area (TPSA), and percent of absorption(%Abs.) were computed using  software Molinspiration. In vitro outcomes, the target compounds were assessed by cell line study for their anticancer effects. All the tested compounds showed the most plausible anticancer activity, when compared to a positive control (atazanavir), using MTT cytotoxic assay, against human prostatic tumor (PC-3), glioma cell line (LN68), and normal WRL-68 cell line.
Conclusion: The results revealed that compounds 2,3,4 and 5 exhibited the highest inhibitory activity against PC3 cell line at IC50 concentrations of 178.2, 75.09, 129.3and 110.5μg/mL, respectively, and they had moderate effects against LN299 cell line at IC50 concentrations 203,172.5, 169,and 157.7 μg/mL, respectively, compared to atazanavir, as a positive control against PC-3, at IC50, 157.3 μg/mL, and in LN299, at IC50 195.7 μg/mL. Also compound (5) attributed to cell-cycle arrest, and induction of apoptosis. The target compounds could be considered as promising as potential anticancer drugs.

Key words: Thiadiazole, phenacyl bromide, molecular binding, docking, HIV1 protease inhibitor.