The College of Pharmacy discussed the MSc thesis entitled “Design, Synthesis, and Preliminary Cytotoxicity Evaluation of 1, 2, 4-Thiadiazole Derivatives as Possible Histone Deacetylase Inhibitors”, by the student Rusul Mohammed Hasan Ali and the supervisor, Associate Professor Dr. Ayad Abed Ali Al-Hamashi, at the Pharmaceutical Chemistry Department. Histone deacetylase (HDAC) enzyme inhibition is a promising approach for treating cancer. The majority of HDAC inhibitors used in clinical settings have a hydroxamate group as a zinc-binding group (ZBG). The poor selectivity and pharmacokinetic properties of several hydroxamate-containing inhibitors have driven the search for non-hydroximic HDAC inhibitors. As a result, the goal of this study is to develop novel HDAC inhibitors that incorporate the thiadiazole moiety as a ZBG. The study included the utilization of the Maestro software in the design and virtual analysis of a series of thiadiazole derivatives as possible HDAC inhibitors. Compounds with acceptable docking scores, which include compounds VIa-VIf, were synthesized by applying traditional chemical reactions. The synthesis was commenced with the ether formation using the Williamson reaction by reacting benzylic halide derivatives with methyl 4-hydroxybenzoate, then the intermediates underwent ester hydrolysis to produce 4-(benzyloxy)benzoic acid derivatives, followed by the amide reaction with 1,2,4-thiadiazol-5-amine to afford final compounds VIa-VIf. A preliminary cytotoxicity study for final compounds was carried out against colon cancer cells using tetrazolium assays. The study showed that the docking scores of VIa – VIf are (−8.953, −9.290, −8.57, −8.784, −8.434, and −8.830 kcal/mol) respectively, while the FDA-approved Vorinostat has a docking score −5.613 kcal/mol against HDAC 2 (4LXZ). The structure for intermediates and final compounds was excellently characterized via Attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR), Nuclear magnetic resonance (NMR), and mass spectroscopy. The cytotoxic effect on colon cancer cells viability test indicated that the IC50 of compounds VIb, VId, and VIf were 1.75, 1.00, and 1.436 µM, respectively while the IC50 for vorinostat was 3.00 µM. New potential HDAC inhibitors with a thiadiazole moiety as a possible zinc-binding group were designed. Molecular docking studies, virtual pharmacokinetic studies, and antiproliferative activity study findings are highly promising, and further structure-activity relationship and biological studies are possibly carried out to validate the current data.
