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
Paula S. Farag; AboulMagd, Asmaa M; Farag, Paula S;
Abstract
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, mo lecular 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.
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, mo lecular 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.
Other data
Title | 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 | Authors | Paula S. Farag ; AboulMagd, Asmaa M; Farag, Paula S | Keywords | 1,3,4-Thiadiazole Thiadiazolo-pyrimidine Green chemistry VEGFR-2 inhibitors Apoptosis Molecular docking | Issue Date | 2021 | Publisher | Elsevier | Journal | Bioorganic Chemistry | Volume | 112 | DOI | 10.1016/j.bioorg.2021.104923 |
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