The College of Pharmacy discussed the PhD dissertation entitled “ Insilico Study, Synthesis, and Preliminary Cytotoxicity Evaluation of New 1,2,4-Triazole-Based Sulfanilamide Derivatives as Possible Carbonic Anhydrase Inhibitors” by the student Mayada Riadh Tawfik and her supervisor Assistant Professor Dr. Mohammed Hassan Mohammed, at the pharmaceutical chemistry department.
The study aimed for the synthesis of new 1,2,4-triazole-based sulfanilamide derivatives using the dual tail approach, as possible carbonic anhydrase inhibitors and their cytotoxicity evaluation against cancer cell lines. In addition to the insilico study that included molecular docking, molecular dynamics and ADME studies.
The study included the synthesis of the NH2 alkylated derivative of sulfanilamide (A), which was then converted into the hydrazide derivative of sulfanilamide (B) that reacted with different para-substituted phenyl isothiocyanates, forming the thiosemicarbazide derivatives of sulfanilamide (C1-C4). Compounds (C1-C4) were subsequently converted into the 1,2,4-triazole derivatives of sulfanilamide (D1-D4), which in turn reacted with different meta-substituted benzyl bromides, forming the SH alkylated derivatives, compounds (P1-P12). The synthesized compounds were characterized by FT-IR, 1H NMR, 13C NMR, and ESI-MS spectroscopic techniques. Cytotoxicity evaluation of (P1-P12) against two cancer cell lines MCF7 and HCT116, in addition to the non-cancerous cell line HFF, was performed using the MTT assay. Molecular docking of the final compounds (P1-P12) was carried out against three carbonic anhydrase isoforms: CA II, CA IX and CA XII using Schrodinger software.
The study concluded that compounds P5 and P6 had significant cytotoxic activity compared to acetazolamide. Moreover, the molecular docking study showed that compound P6 had good binding affinity toward CA IX compared to the other two isoforms, indicating a promising selectivity for CA IX by using the dual tail approach and improving binding with surrounding residues in the hydrophobic and hydrophilic regions.
The study recommended that it is important to do more in vitro cytotoxicity evaluation on different cancer cell lines in hypoxic conditions. In addition, studying the enzymatic selectivity of the target compounds against different isoforms of the enzyme.
