Structural insights and cytotoxicity evaluation of benz[e]indole pyrazolyl-substituted amides

Document Type

Article

Publication Date

6-1-2024

Abstract

Five new compounds of benze]indole pyrazolyl-substituted amides (2a-e) were synthesised in low to good yields via the direct amide-coupling reaction between a pyrazolyl derivative containing a carboxylic acid and several amine substrates. The molecular structures were determined by various spectroscopic methods, such as NMR (H-1, C-13 and F-19), FT-IR and high-resolution mass spectrometry (HRMS). X-ray crystallographic analysis on the 4-fluorobenzyl derivative (2d) reveals the amide -O atom to reside to the opposite side of the molecule to the pyrazolyl-N and pyrrolyl-N atoms; in the molecular packing, helical chains feature amide-N?H?N(pyrrolyl) hydrogen bonds. Density-functional theory (DFT) at the geometry optimisation B3LYP/6-31G(d) level on the full series shows general agreement with the experimental structures. While the LUMO in each case is spread over the benze]indole pyrazolyl moiety, the HOMO spreads over the halogenated benzosubstituted amide moieties or is localised near the benze]indole pyrazolyl moieties. The MTT assay showed that 2e, exhibited the highest toxicity against a human colorectal carcinoma (HCT 116 cell line) without appreciable toxicity towards the normal human colon fibroblast (CCD-18Co cell line). Based on molecular docking calculations, the probable cytotoxic mechanism of 2e is through the DNA minor groove binding.

Keywords

X-ray crystallography, DFT, Cytotoxicity, Minor groove binding

Publication Title

Molecular Diversity

Divisions

InstituteofBiologicalSciences,CHEMISTRY,nanotechnology

Funders

Universiti Sains Malaysia (304/PKIMIA/6315738),Sunway University Sdn Bhd (GRTIN-RRO-56-2022)

Volume

28

Issue

3

Publisher

Kluwer (now part of Springer)

Publisher Location

VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS

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