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 pchlorobenzaldehyde 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 1,3,4thiadiazole 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 mu M. 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 mu M 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.

Automated summary

A green and efficient method was developed for the synthesis of 1,3,4-thiadiazole derivatives with broad-spectrum cytotoxic activity against multiple cancer cell lines. Several compounds exhibited significant inhibitory activity against VEGFR-2 kinase and strong DNA-binding affinity.