Synthesis, and Cytotoxic Activity of Novel Pyrazoline-Thiazolidinone Derivatives with Molecular Docking Studies

Abstract

1-(4-substitutesd)-2-(5-phenyl-3-(1H-pyrrol-2-yl)-4,5-dihydropyrazol-1-yl)thiazol-5-yl)-2-aryldiazene 9a-f were prepared through reactions of 5-phenyl-3-(1H-pyrrol-2-yl)-4, 5-dihydropyrazole-1-carbothioamide 5 with hydrazonoyl halides. Furthermore, thioamide 5 was utilized as starting materials for thiazolidone synthesis 10 and arylidene thiazoles 15a–c. Also pyran derivatives 12a-b, 13a-b,14a-b and thioanilide derivaives 16 were obtained from the reaction of thiazilidone 10 with arylidenemalononitrile and phenyl isothiocyanat, respectively. When possible, the structures of experimentally synthesized compounds were identified by elemental analysis, spectral analysis, and alternative synthesis routes. Some of the synthesized compounds as 9f, 10, 12b, and 16 were screened for their cytotoxicity against MCF-7 and HCT-116 cells using the MTT assay. They exhibited remarkable cytotoxic activities with promising IC₅₀ values. Interestingly, compound 16 exhibited potent cytotoxicity against MCF-7 and HCT-116 with IC₅₀ values of 5.05 and 3.08 μM, compared to doxorubicin with IC₅₀ values of 7.27 and 8.92 μM, respectively show interesting biological activities as anticancer activities. Additionally, the tested compounds were nontoxic against WISH cells with higher IC₅₀ values. Hence, these compounds may serve as potent and selective cytotoxic agents.

Graphical Abstract

Keywords:

• Pyrazoline-Thiazolidinone
• cytotoxicity
• docking

Acknowledgments

The authors of this manuscript have all been generously assisted, supervised, and tutored by the late Prof. Dr. Abdo Osman Abdelhamid - Chemistry Department - Cairo University, and for this, we would gladly like to dedicate this acknowledgment to his soul. We will always remember and be thankful for the non-ending guidance and support that we witnessed through his long generous journey. With grateful hearts, we will always pray that his soul may rest in pea

Disclosure statement

The authors declare that they have no conflict of interest.

Figure 2. ADME pharmacokinetics of the most active compound 16 using A: SWIS-ADME. B: Drug likeness score of compound 16 using MolSoft “The green color denotes non-drug-like behavior, while the blue color denotes drug-like behavior. Compounds with a negative or zero value should not be considered drug-like and C: BOILED-Egg model for compound 16 using SwissADME “Points in the BOILED-yolk Egg's are molecules predicted to passively permeate the blood–brain barrier (BBB), whereas points in the BOILED-white Egg's are molecules predicted to be passively absorbed by the GI tract.”

Figure 3. Molecular docking results, A: Surface representation of the co-crystallized ligand (Cyan-colored) and the docked compound 16 (yellow-colored) highlighting the binding mode. B: Two-dimentaional interaction modoe, and C: the three-dimensional ineteraction mode with Lys 89 as the key amino acid inside the CDK-2 kinase protien (PDB = 2a4l). Two-dimentional for all compounds are supported as supplementary.