Objective: In this study, a series of novel 2,3-disubstituted quinazolines (4a-4l) were synthesized using standard procedures and elucidated through different spectroscopic techniques. Methods: Obtained compounds were evaluated for their cytotoxicity against human breast cancer (MDA-MB-231) and ovarian cancer (SK-O-V3) cell lines using MTT assay. Docking studies with JAK2 protein were performed to elucidate the possible mechanistic insights into these novel quinazoline derivatives. Results: Moderate-to-good in vitro cytotoxic potentials of the newly synthesized molecules were reported against selected human cancer cell lines. Among the tested molecules, compound 4e showed good cytotoxic activity against MD-AMB-231 (14.2 ± 0.86 μM) and against SK-O-V3 (17.7 ± 0.62 μM). Conclusion: The in vitro studies of the newly synthesized quinazoline derivatives reported considerable cytotoxic potentials against both breast and ovarian cancer cell lines and SAR studies suggest that quinazoline derivatives with heterocyclic benzothiazole nucleus with hydrophilic acetamide linkage at the 3rd position could probably increase the cytotoxic potentials and the presence of chlorine substitution could add more benefit. With the reported bioactivities of these derivatives, further studies on the derivatization could elucidate the broader cytotoxic potentials.

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Objective: The involvement of Janus kinase2/signal transducer and activator of transcription (JAK2/STAT3) pathway reported in various solid tumors made authors study the conformational changes of JAK2-3e complex which was previously reported with a moderate percentage of In-vitro JAK2 inhibition. Methods: In this present study Compound 3e was reported with a moderate percentage of inhibition of JAK2 protein selected for performing molecular docking and molecular dynamics studies to elucidate the conformational changes with JAK2-3e complex. Docking studies were performed using ChemSketch to draw the structure of the compound and optimized/energy minimized using the Ligprep module of Schrodinger suite, employing optimized potentials for liquid simulations (OPLS-2005) force field. Molecular dynamics simulations were performed for 10 ns for complex using TIP4PEW water solvent model and neutralized by adding sodium ions. Results: Docking studies of Compound 3e which has been reported as one of the effective cytotoxic agents and a moderate percentage of In-vitro JAK2 inhibition among the series, showed H-bond interaction with leucine 855, serine936, aspartine994. Dock score and Ligand binding energy with protein suggested compound 3e has shown-4.049,-66.003 kcal/mol respectively. Molecular dynamics simulations elucidated the mechanistic insight of JAK-2 inhibition. The Root means square deviation (RMSD) pattern of both protein and ligands in the JAK2-3e complex observed to be different over 10 ns simulation. In the JAK2-3e complex, an exponential increase in RMSD of Cα and side-chain amino acids is observed during the first 1-3 ns simulation and is stabilized till 10 ns. During the 10 ns simulation, ligand 3e seems to be stable in the complex with an overall deviation<1 Å, despite a drastic increase between 1-3 ns. The ligand RMSD plot suggests that the ligand 3e remained intact within the binding site of the protein and longer time period simulation may elucidate the binding pattern and fate of ligand 3e. Conclusion: Results from molecular dynamics simulations elucidated the mechanistic insight of JAK-2 inhibition by 2, 4 disubstituted quinazoline compound that is N’(2-(4-nitrophenyl)quinazoline-4-yl) isonicotinohydrazide) and their binding phenomenon. Molecular docking studies further supported the elucidation of binding patterns of the molecules in the JAK-2 protein environment. Further simulations with a longer time period may provide deeper insights into ligand interactions in the protein environment. It is noteworthy to use compound 3e as a new scaffold for further development of multifunctional compounds.