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

• Published in: Molecular diversity Vol. 28; no. 3; pp. 1363 - 1376
• Main Authors: Ramle, Abdul Qaiyum, Chan, Nadia Nabihah Mohd Yusof, Ng, Min Phin, Tan, Chun Hoe, Sim, Kae Shin, Tiekink, Edward R. T., Fei, Chee Chin
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2024; Springer Nature B.V
• Subjects: Amides - chemistry; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemistry; Biomedical and Life Sciences; Cell Line, Tumor; Cell Survival - drug effects; Crystallography, X-Ray; HCT116 Cells; Humans; Indoles - chemistry; Indoles - pharmacology; Life Sciences; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Organic Chemistry; Original Article; Pharmacy; Polymer Sciences; Pyrazoles - chemistry; Pyrazoles - pharmacology; Structure-Activity Relationship; Toxicity; X-ray crystallography; Cytotoxicity; DFT; Minor groove binding
• ISSN: 1381-1991; 1573-501X
• DOI: 10.1007/s11030-023-10662-2

Five new compounds of benz[ e ]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 ( 1 H, 13 C and 19 F), 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 benz[ e ]indole pyrazolyl moiety, the HOMO spreads over the halogenated benzo-substituted amide moieties or is localised near the benz[ e ]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. Graphical abstract