668980-81-2Relevant articles and documents
In-Silico Screening of Novel Synthesized Thienopyrimidines Targeting Fms Related Receptor Tyrosine Kinase-3 and Their In-Vitro Biological Evaluation
Alkahtani, Manal Mubarak,Altwaijry, Najla,Attallah, Nashwah G. M.,Elmongy, Elshaymaa I.,Henidi, Hanan Ali
, (2022/02/07)
The present investigation describes the design strategy and synthesis of novel thienopyrimidine compounds in addition to their anticancer activity targeting tyrosine kinase FLT3 en-zyme. The synthesized compounds were subjected to a cytotoxic study where compounds 9a and 9b showed the most potent cytotoxicity against HT-29, HepG-2, and MCF-7 cell lines reflected by their IC50 values for 9a (1.21 ± 0.34, 6.62 ± 0.7 and 7.2 ± 1.9 μM), for 9b (0.85 ± 0.16, 9.11 ± 0.3 and 16.26 ± 2.3 μM) and better than that of reference standard which recorded (1.4 ± 1.16, 13.915 ± 2.2, and 8.43 ± 0.5 μM), respectively. Compounds’ selectivity to malignant cells was determined using selectivity assay, interestingly, all the tested compounds demonstrated an excellent selectivity index (SI) range from 20.2 to 99.7. Target in-silico prediction revealed the FLT3 kinase enzyme was the kinase enzyme of highest probability. Molecular docking studies were performed on the pre-pared compounds which showed promising binding affinity for FLT3 kinase enzyme and the main interactions between the synthesized ligands and kinase active site were similar to those between the co-crystallized ligand and the receptor. Further biological exploration was performed using in-vitro FLT3 kinase enzyme inhibition assay. The results showed that the 2-morpholinoacetamido derivative 10a exhibited highest FLT3 inhibitory activity among the tested compounds followed by compound 9a then 12. Pharmacokinetic assessment disclosed that all the investigated compounds were considered as “drug-like” molecules with promising bioavailabil-ity.
