Synthesis, biological evaluation and in silico studies of azo-based calix[4]arenes

Abstract

Calix[n]arenes are cyclic oligomers that were initially obtained from the condensation of phenols and formaldehyde. Calixarene modifications produce various useful derivatives with numerous applications. Azo calixarenes are obtained by incorporation of one or more azo units at the upper rim and/or lower rim of calixarene. Applications of azo calixarenes are observed in various fields such as agriculture, biotechnology and in the development of optical devices, chemical sensor devices, and luminescence probes. However, their potential use as pharmaceutical agents has not been fully explored. The present study aimed to synthesise and explore the biological potentials of azo calix[4]arenes. Both upper and lower rim-modified azo calix[4]arenes were synthesised, characterised and evaluated for their antibacterial, antifungal and antiproliferative activities. In order to keep the molecular weight in possible minimum range, selective modification of calix[4]arene scaffold was adopted for certain compounds and mono and di-substituted products were obtained in good yields. Compounds obtained from sulphanilamide, sulfaguanidine and 2-methyl-4-aminobenzoic acid showed good activity against bacterial strains with MIC values ranging from 0.97-62.5 µg/mL. In cytotoxicity assay, 4-phenylazobenzoyl chloride was the most active compounds against the examined four cancer cell lines (MCF-7, MDA-MB-231, HCT-116 and A549), with IC50 value ranging from 15.56 to 21.4 µM. Moderate activity was shown by azo calix[4]arenes containing sulfonamide group. In silico study (molecular docking) was performed to see the interaction of the designed compounds with targeted proteins (PDB IDs 4CJN, 1CEF, 1FVT, 3TI6 and 1ZXM). Some of the azo calix[4]arenes showed good interaction with the active site of microbial and/or human enzymes through hydrogen, hydrophobic and pi-pi interactions, and could inhibit the activity of these enzymes. Among the five receptors, the compounds showed more affinity towards penicillin-binding proteins (PDB IDs 4CJN and 1CEF) that suggested their prospective antibacterial activity.