BRAF-Targeted Anticancer Agents: Synthesis, Molecular Docking, and In Vitro Evaluation of Novel 1,3,4-Thiadiazolyl-Benzamide Derivatives
Indhumathy P., Gandhimathi RathinasamyObjective:
This study describes the design, synthesis, and biological evaluation of a novel series of 1,3,4-thiadiazolyl-benzamide derivatives as potential BRAF-targeted anticancer agents.
Methods:
N2-(Pyridin-3-ylmethyl)-1,3,4-thiadiazole-2,5-diamine was reacted with a series of aromatic aldehydes through Schiff base condensation to synthesize the target derivatives. The synthesized compounds were structurally characterized using appropriate spectroscopic techniques. Molecular docking studies were performed using the BRAF kinase crystal structure (PDB ID: 4LMN), and the drug-likeness and pharmacokinetic properties of the synthesized compounds were evaluated using in silico ADME profiling.
Results:
Molecular docking studies revealed that compounds M13, M2, M3, and M17 exhibited favorable interactions within the ATP-binding site of BRAF kinase. Among these compounds, M13 showed the most favorable docking score (−9.20 kcal/mol), although its predicted binding affinity was lower than that of the reference drug dabrafenib (−11.24 kcal/mol). In silico ADME analysis indicated that the synthesized compounds generally exhibited favorable drug-likeness, with no violations of Lipinski's rule of five and high predicted gastrointestinal absorption. In the MTT assay, M13 demonstrated potent antiproliferative activity against the M14 and B16-F1 cell lines, with IC50 values of 29.30 ± 0.36 and 31.19 ± 0.01 nM, respectively.
Discussion:
The synthesized 1,3,4-thiadiazolyl-benzamide derivatives demonstrated promising antiproliferative activity. Among the evaluated compounds, M13 exhibited the most favorable overall profile, supported by its favorable molecular docking interactions with BRAF kinase and acceptable predicted ADME properties. The biological findings further support the potential of this scaffold for the development of BRAF-targeted anticancer agents.
Conclusion:
The findings suggest that 1,3,4-thiadiazolyl-benzamide derivatives, particularly M13, represent promising chemical scaffolds for further development as BRAF-targeted anticancer agents for melanoma. Further biological and pharmacological investigations are warranted to validate their BRAF inhibitory activity and therapeutic potential.