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. 2024 Nov 14;18(1):228.
doi: 10.1186/s13065-024-01346-5.

New thiophene derivatives: chemoselective synthesis, antitumor effectiveness, structural characterization, DFT calculations, Hirshfeld surface, and Fukui function analysis

Abdullatif Bin Muhsinah  1 , Mohammed M Alharbi  2 , Nabila A Kheder  3 , Saied M Soliman  4 , Hazem A Ghabbour  5 , Naglaa S Mahmoud  6 , Ismail A Elhaty  7 , Yahia N Mabkhot  8
Affiliations

New thiophene derivatives: chemoselective synthesis, antitumor effectiveness, structural characterization, DFT calculations, Hirshfeld surface, and Fukui function analysis

Abdullatif Bin Muhsinah et al. BMC Chem. .

Abstract

In this study, the chemoselective synthesis of two new thiophene derivatives is presented. The structure of newly synthesized thiophenes derivatives; ethyl 4-acetyl-3-phenyl-5-(phenylamino)thiophene-2-carboxylate (5) and ethyl (E)-4-(3-(dimethylamino)acryloyl)-3-phenyl-5-(phenylamino)thiophene-2-carboxylate (8) were established using different FTIR and NMR spectral analyses. Compound 8 was isolated as single crystal and its 3D structure was determined using X-ray crystallographic analysis. Possible intermolecular interactions that control the molecular packing of 8 were elucidated using Hirshfeld topology analysis. The O…H (13.7%), H…H (55.3%) and C…C (2.3%) intermolecular interactions are the most significant. Fukui functions showed that C4 in thiophene 5 and C3 in thiophene 8 are the most reactive atoms for nucleophilic attack, while N9 in thiophene 5 and C1 in thiophene 8 are the most reactive atoms for electrophilic attack. Antitumor activity of thiophene 5 was assessed and the results showed higher activity against HepG-2 (7.46 µg/mL) compared to the HCT 116 (12.60 µg/mL) cell line.

Keywords: Antitumor activity; Chemoselective synthesis; DFT calculations; Fukui function; Hirshfeld surface analysis; Thiophene; X-ray crystallography.

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Conflict of interest statement

Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Chemical structures of some medications incorporate thiophene nucleus
Scheme 1
Scheme 1
A mechanistic pathway to thiophene derivatives 5
Fig. 2
Fig. 2
Chemical structures of possible reaction products
Scheme 2
Scheme 2
Synthetic approach to thiophene 8
Fig. 3
Fig. 3
ORTEP diagram of thiophene 8
Fig. 4
Fig. 4
Molecular packing of compound 8 along a and c axes
Fig. 5
Fig. 5
Hirshfeld dnorm maps (I), all contacts and their percentages (II), and fingerprint plots for the important contacts (III) for thiophene 8
Fig. 6
Fig. 6
Shape index and curvedness maps for thiophene derivative 8
Fig. 7
Fig. 7
The optimized geometry (A) and its overlay with the X-ray structure (B)
Fig. 8
Fig. 8
The MEP map for thiophene derivative 8
Fig. 9
Fig. 9
The HOMO and LUMO levels for 8
Fig. 10
Fig. 10
The optimized structures of thiophene 5 (a) and 8 (b)
Fig. 11
Fig. 11
Viability values of Doxorubicin (Dox) and thiophene 5 against HCT-116 and HepG-2 cell lines
See this image and copyright information in PMC

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