Design, microwave assisted synthesis, and molecular modeling study of some new 1,3,4-thiadiazole derivatives as potent anticancer agents and potential VEGFR-2 inhibitors.

A green and efficient method was developed for the synthesis of 1,3,4-thiadiazole based compounds under microwave (MW) activation. The nucleophile N-(5-amino-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamide (3) was synthesized and reacted with different carbon electrophilic reagents to afford thiadiazolo-pyrimidine or imidazolo-thiadiazoline derivatives (4-6 and 8), respectively. Furthermore, a one-pot reaction of 3 with p-chlorobenzaldehyde and different carbon electrophile/ or nucleophiles under microwave irradiation yields the cyclic thiadiazolo-pyrimidine derivatives 10-15. Additionally, nucleophilic substitution of aromatic amines and/or potassium salts of some heterocyclic compounds with chloroacetamido-thiadiazole 6 yields derivatives 16-20. All the new derivatives were synthesized by both conventional and MW irradiation methods. All the new 1,3,4-thiadiazole derivatives were evaluated against four cancer cell lines, HepG-2, MCF-7, HCT-116, and PC-3. The anti-proliferative activity of most of the synthesized compounds exhibited excellent broad-spectrum cytotoxic activity against the cancer cell lines with IC50 values ranging from 3.97 to 9.62 μM. Moreover, the enzymatic assessment of five derivatives (2,4b, 6, 8, 9a) against VEGFR-2 tyrosine kinase showed significant inhibitory activities with IC50 of 11.5, 8.2, 10.3, 10.5 and 9.4 nM respectively. Further studies revealed the ability of compound 9a to have a strong DNA-binding affinity of 36.06 μM via DNA/methyl green assay. Moreover, molecular docking study was carried out to reveal the binding interactions of compounds in the binding site of VEGFR-2 enzyme explaining the significant inhibitory activity of these derivatives. Finally, ADME/Tox studies was performed to predict the pharmacokinetics of the synthesized compounds.