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Synthesis, Anticancer Activities and Molecular Docking Studies of a Novel Class of 2-Phenyl-5,6,7,8-tetrahydroimidazo [1,2-b]pyridazine Derivatives Bearing Sulfonamides.

ABSTRACT: In the present study, new 2-phenyl-5,6,7,8-tetrahydroimidazo [1,2-b]pyridazines bearing sulfonamides were synthesized, characterized and evaluated for their anticancer activities. The structures of these derivatives were elucidated by ¹H NMR, ¹³C NMR, infrared and high-resolution mass spectrometry for further validation of the target compound structures. The anticancer activities of the new molecules were evaluated against five human cancer cell lines, including A-549, Hs-683, MCF-7, SK-MEL-28 and B16-F10 cell lines using 5-fluorouracil and etoposide as the reference drugs. Among the tested compounds, 4e and 4f exhibited excellent activities in the same range of the positive controls, 5-fluorouracil and etoposide, against MCF-7 and SK-MEL-28 cancer cell lines, with IC₅₀ values ranging from 1 to 10 μM. The molecular docking studies of 4e and 4f showed a strong binding with some kinases, which are linked to MCF-7 and SK-MEL-28 cancer cell lines.

SUBMITTER: Bourzikat O

PROVIDER: S-EPMC9416205 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Synthesis, Anticancer Activities and Molecular Docking Studies of a Novel Class of 2-Phenyl-5,6,7,8-tetrahydroimidazo [1,2-b]pyridazine Derivatives Bearing Sulfonamides.

Bourzikat Otmane O El Abbouchi Abdelmoula A Ghammaz Hamza H El Brahmi Nabil N El Fahime Elmostfa E Paris Arnaud A Daniellou Richard R Suzenet Franck F Guillaumet Gérald G El Kazzouli Saïd S

Molecules (Basel, Switzerland) 20220817 16

In the present study, new 2-phenyl-5,6,7,8-tetrahydroimidazo [1,2-b]pyridazines bearing sulfonamides were synthesized, characterized and evaluated for their anticancer activities. The structures of these derivatives were elucidated by 1H NMR, 13C NMR, infrared and high-resolution mass spectrometry for further validation of the target compound structures. The anticancer activities of the new molecules were evaluated against five human cancer cell lines, including A-54 ...[more]

PMID: 36014478

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Project description:ObjectivesThe goal of this study was to design and enable development of anticancer sulfonamides by coupling amines and dansyl chloride with strategically selected substituents. The synthesized structures were characterized by NMR and mass spectrometry. In addition, molecular docking analysis was used to determine the binding ability of sulfonamides toward 1AZM, a possible drug target, as compared with that of the well-known drug acetazolamide.MethodsSulfonamides were synthesized by coupling amines and dansyl chloride under highly favorable conditions. The designed sulfonamides incorporated strategically positioned substituents to impart diverse biological properties. The synthesized structures were validated with NMR and mass spectra. Molecular docking analysis was performed to evaluate the binding affinities of the synthesized sulfonamides with the potential drug target 1AZM.ResultsThe synthesis of sulfonamides through the coupling of amines and dansyl chloride was successfully achieved. The validation of the synthesized structures with NMR and mass spectra confirmed their chemical identities. Molecular docking analysis revealed that the synthesized sulfonamides displayed binding affinities ranging from -6.8 to -8.2 kcal/mol toward the potential drug target 1AZM. Importantly, all derivatives exhibited superior binding affinities to acetazolamide (-5.25 kcal/mol).ConclusionsThe coupling of amines and dansyl chloride enabled efficient, straightforward sulfonamide synthesis. The strategic design of sulfonamides with specific substituents endows diverse biological properties, including potential anti-cancer activity. The elucidation of the synthesized compounds with NMR and mass spectra confirmed their structures. Molecular docking analysis demonstrated that the synthesized sulfonamides exhibited favorable binding affinities toward the potential drug target 1AZM. Notably, all derivatives displayed higher binding affinities, ranging from -6.8 to -8.2 kcal/mol, than the recommended drug acetazolamide (-5.25 kcal/mol), thus suggesting their potential as highly effective analogues for further validation in cancer therapy.

Project description:The development of new approaches for the synthesis of new bioactive heterocyclic derivatives is of the utmost importance for pharmaceutical industry. In this regard, the present study reports the green synthesis of new benzaldazine and ketazine derivatives via the condensation of various carbonyl compounds (aldehydes and ketones with the 3-(1-hydrazineylideneethyl)-1H-indole using the grinding method with one drop of acetic acid). Various spectroscopic techniques were used to identify the structures of the synthesized derivatives. Furthermore, the anticancer activities of the reported azine derivatives were evaluated against colon, hepatocellular, and breast carcinoma cell lines using the MTT technique with doxorubicin as a reference medication. The findings suggested that the synthesized derivatives exhibited potential anti-tumor activities toward different cell lines. For example, 3c, 3d, 3h, 9, and 13 exhibited interesting activity with an IC50 value of 4.27-8.15 µM towards the HCT-116 cell line as compared to doxorubicin (IC50 = 5.23 ± 0.29 µM). In addition, 3c, 3d, 3h, 9, 11, and 13 showed excellent cytotoxic activities (IC50 = 4.09-9.05 µM) towards the HePG-2 cell line compared to doxorubicin (IC50 = 4.50 ± 0.20 µM), and 3d, 3h, 9, and 13 demonstrated high potency (IC50 = 6.19-8.39 µM) towards the breast cell line (MCF-7) as compared to the reference drug (IC50 = 4.17 ± 0.20 µM). The molecular interactions between derivatives 3a-h, 7, 9, 11, 13, and the CDK-5 enzyme (PDB ID: 3IG7) were studied further using molecular docking indicating a high level of support for the experimental results. Furthermore, the drug-likeness analysis of the reported derivatives indicated that derivative 9 (binding affinity = -8.34 kcal/mol) would have a better pharmacokinetics, drug-likeness, and oral bioavailability as compared to doxorubicin (-7.04 kcal/mol). These results along with the structure-activity relationship (SAR) of the reported derivatives will pave the way for the design of additional azines bearing indole with potential anticancer activities.

Dataset Information

Synthesis, Anticancer Activities and Molecular Docking Studies of a Novel Class of 2-Phenyl-5,6,7,8-tetrahydroimidazo [1,2-b]pyridazine Derivatives Bearing Sulfonamides.

Publications

Synthesis, Anticancer Activities and Molecular Docking Studies of a Novel Class of 2-Phenyl-5,6,7,8-tetrahydroimidazo [1,2-<i>b</i>]pyridazine Derivatives Bearing Sulfonamides.

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