Metal-free domino amination-Knoevenagel condensation approach to access new coumarins as potent nanomolar inhibitors of VEGFR-2 and EGFR

Abstract

A metal-free, atom-economy and simple work-up domino amination-Knoevenagel condensation approach to construct new coumarin analogous (4a-f and 8a-e) was described. Further, new formyl (5a,d-f) and nitro (9a,d-f) coumarin derivatives were synthesized via C-N coupling reaction of various cyclic secondary amines and 4-chloro-3-(formyl-/nitro)coumarins (1a,c), respectively. The confirmed compounds were screened for their in vitro anti-proliferative activity against KB-3-1, A549 and PC3 human cancer cell lines using resazurin cellular-based assay. Among them, coumarin derivatives 4e and 8e displayed the best anti-cervical cancer potency (KB-3-1) with IC 50 values of 15.5 ± 3.54 and 21 ± 4.24 µM, respectively. Also, 4e showed the most promising cytotoxicity toward A549 with IC 50 value of 12.94 ± 1.51 µM. As well, 9d presented a more significant impact of potency against PC3 with IC 50 7.31 ± 0.48 µM. Moreover, 8d manifested selectivity against PC3 (IC 50 = 20.16 ± 0.07 µM), while 8e was selective toward KB-3-1 cell line (IC 50 = 21 ± 4.24 µM). Matching with docking profile, the enzymatic assay divulged that 8e is a dual potent single-digit nanomolar inhibitor of VEGFR-2 and EGFR with IC 50 values of 24.67 nM and 31.6 nM that were almost equipotent to sorafenib (31.08 nM) and erlotinib (26.79 nM), respectively.

Tailoring of novel morpholine-sulphonamide linked thiazole moieties as dual targeting DHFR/DNA gyrase inhibitors: synthesis, antimicrobial and antibiofilm activities, and DFT with molecular modelling studies

“…A molecular docking simulation was then performed to acquire insight into the interactions and binding mechanism of active 4-thiazolone 7 into the active sites of E. coli DNA gyrase (PDB ID: ) and E. coli DHFR (PDB ID: ). The i GEMDOCK software version 2.1 31,46–48 was used to perform molecular docking, and the results are outlined in Table 5. As depicted in Fig.…”

“…Flexible docking simulation was performed by i GEMDOCK software version 2.1 (Department of Biological Science and Technology and Institute of Bioinformatics, National Chiao Tung University, Taiwan), as previously documented. 31,47,48 Accurate docking based on a generic evolutionary protocol (GA) and an empirical scoring function was applied to investigate the interaction fashions between the active thiazole 7 and E. coli DNA gyrase (PDB ID: ) and E. coli DHFR (PDB ID: ) as biological targets.…”

New edaravone analogs incorporated with N‐benzylthiazole moiety: Multistep chemical synthesis, in vitro cytotoxicity with pRIPK3 inhibitory activities, and molecular docking

“…A flexible molecular docking simulation was then performed to acquire insight into the interactions and binding mechanism of active N-phenylpyrazolone-Nbenzylthiazole hybrids (3 and 4b) into the active domain of RIPK3 (PDB ID: 7MX3) kinase as an important targeted therapy. The iGEMDOCK software version 2.1 [23,35,36] was used to perform molecular docking, and the results are outlined in Table 4. As depicted in Figure 6A-C, compound 3 that bears an N-benzyl-4-thiazolone moiety is aligned in the active site of RIPK3 with a fitness value of À123.382 kcal/mol through different intermolecular forces, including van der Waals (London forces), hydrophobic interactions, and one conventional H-bond.…”

Development of certain benzylidene coumarin derivatives as anti-prostate cancer agents targeting EGFR and PI3Kβ kinases

“…Coumarin derivative V showed high EGFR inhibition impact, demonstrating 97.67% erlotinib’s potency along with the high cytotoxic activity over MDA-MB-231 27 . In addition, compound VI possessed high EGFR inhibitory activity and high cytotoxic activity against cervical cancer 28 . By optimising coumarin as the primary scaffold ( Figure 2 ), a novel series of coumarin derivatives was discovered in the current study.…”