In-Silico Screening of Novel Synthesized Thienopyrimidines Targeting Fms Related Receptor Tyrosine Kinase-3 and Their In-Vitro Biological Evaluation

• Main Authors: Elshaymaa I. Elmongy (Author), Najla Altwaijry (Author), Nashwah G. M. Attallah (Author), Manal Mubarak AlKahtani (Author), Hanan Ali Henidi (Author)
• Format: Book
• Published: MDPI AG, 2022-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph15020170; 1424-8247
• Keywords: thienopyrimidines; selectivity index; in-silico screening; tyrosine kinase enzyme; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 15, Iss 2, p 170 (2022)

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 <b>9a</b> and <b>9b</b> showed the most potent cytotoxicity against HT-29, HepG-2, and MCF-7 cell lines reflected by their IC₅₀ values for <b>9a</b> (1.21 ± 0.34, 6.62 ± 0.7 and 7.2 ± 1.9 μM), for <b>9b</b> (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 <b>10a</b> exhibited highest FLT3 inhibitory activity among the tested compounds followed by compound <b>9a</b> then <b>12</b>. Pharmacokinetic assessment disclosed that all the investigated compounds were considered as "drug-like" molecules with promising bioavailability.