| Autor: |
Elmongy EI; Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh 84428, Saudi Arabia.; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo 11795, Egypt., Altwaijry N; Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh 84428, Saudi Arabia., Attallah NGM; Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh 84428, Saudi Arabia.; Egyptian Drug Authority (EDA) (Previously NODCAR), Giza 8655, Egypt., AlKahtani MM; Research Department, Health Sciences Research Center, Princess Nourah Bint Abdulrahman University, Riyadh 84428, Saudi Arabia., Henidi HA; Research Department, Health Sciences Research Center, Princess Nourah Bint Abdulrahman University, Riyadh 84428, Saudi Arabia. |
| Abstrakt: |
The present investigation describes the design strategy and synthesis of novel thienopyrimidine compounds in addition to their anticancer activity targeting tyrosine kinase FLT3 enzyme. 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 IC 50 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 prepared 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 bioavailability. |
