Synthesis of thiophene-appended pyrazolines via citrus juice-assisted cyclocondensation: Characterization, crystal studies, computational analysis, and anti-angiogenic potential

Chandan, M. and Udaya, K. A. H. and Mahesha and Rekha, N. D. and Deepashree, N. (2025) Synthesis of thiophene-appended pyrazolines via citrus juice-assisted cyclocondensation: Characterization, crystal studies, computational analysis, and anti-angiogenic potential. Journal of Molecular Structure, 1344. ISSN 00222860

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Abstract

A series of thiophene-tethered pyrazoline derivatives (5a-h) were synthesized via a green cyclocondensation reaction between chalcones and substituted phenylhydrazines, utilizing citrus fruit extract as an environmentally benign reaction medium. The compounds were obtained in yields ranging from 72 to 89 %. Structural characterization was performed using 1H and 13C NMR spectroscopy and mass spectrometry, while compound 5 g was further characterized by single-crystal X-ray diffraction, revealing an envelope conformation with distinct dihedral angles of 6.78°, 10.77°, and 88.6° between the pyrazoline and attached aromatic rings. Hirshfeld surface analysis revealed dominant H···H and C···H interactions in the crystal packing, while energy framework analysis indicated that dispersion energy (-249.8 kJ/mol) was the most significant stabilizing factor. Density Functional Theory (DFT) calculations (APFD/6–311++G(d,p)) showed that compound 5h exhibited the lowest HOMO–LUMO gap (3.17 eV), highest electron affinity (1.82 eV), and lowest ionization potential (4.99 eV), suggesting high reactivity, while compound 5f was the most electronically stable. Electrostatic potential maps of 5 g and 5 h indicated regions of strong nucleophilic and electrophilic potential. Anti-angiogenic activity was evaluated using the chorioallantoic membrane (CAM) assay, where compounds 5a, 5c, 5 g, and 5 h significantly reduced microvessel density compared to control groups. Molecular docking studies against the c-Met tyrosine kinase receptor revealed strong binding affinities, with docking scores ranging from -6.7 to -9.1 kcal/mol. Compound 5c, with the highest theoretical pKd value of 6.68, demonstrated the strongest binding affinity, while compound 5a formed a key hydrogen bond with ASP1046, with the centroid of its pyrazoline ring positioned 2.78 Å from the receptor, indicating a stable interaction. These findings highlight the potential of thiophene-linked pyrazolines as promising candidates for anti-angiogenic drug development. © 2025 Elsevier B.V.

Item Type:	Article
Uncontrolled Keywords:	C-MET receptor; DFT calculations; Green synthesis; Pyrazolines;Thiophene; X-ray diffraction
Subjects:	C Chemical Science > Chemistry
Divisions:	Department of > Chemistry
Depositing User:	Vasantha library uom
Date Deposited:	28 Nov 2025 07:34
Last Modified:	28 Nov 2025 07:34
URI:	http://eprints.uni-mysore.ac.in/id/eprint/18080

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