No abstract

Background: Sulfonamides have been in clinical use for many years and the development of bioactive substances containing the sulfonamide subunit has grown steadily in view of their important biological properties such as antibacterial, antifungal, antiparasitic, antioxidant and antitumour properties. Objective: This review addresses the medicinal chemistry aspects of sulfonamides; covering their discovery, the structureactivity relationship and the mechanism of action of the antibacterial sulfonamide class, as well as the physico-chemical and pharmacological properties associated with this class. It also provides an overview of the various biological activities inherent to sulfonamides, reporting research that emphasises the importance of this group in the planning and development of bioactive substances, with a special focus on potential antitumour properties. Discussion: The synthesis of sulfonamides is considered to be simple and provides a diversity of derivatives from a wide variety of amines and sulfonyl chlorides. The sulfonamide group is a non-classical bioisostere of carboxyl groups, phenolic hydroxyl groups and amide groups. This review highlights that most of the bioactive substances have the sulfonamide group, or a related group such as sulfonylurea, in an orientation towards other functional groups. This structural characteristic was observed in molecules with distinct antibacterial activities, demonstrating a clear structureactivity relationship of sulfonamides. Conclusion: This short review sought to contextualise the discovery of classic antibacterial sulfonamides and their physico-chemical and pharmacological properties. The importance of the sulfonamide subunit in Medicinal Chemistry has been highlighted and emphasised, in order to promote its inclusion in the planning and synthesis of future drugs.

Using molecular hybridization, specific sulfonamide derivatives of eugenol were synthesized with subtle modifications in the allylic chain of the eugenol subunit (and also in the nature of the substituent group in the sulfonamide aromatic ring) which allowed us to study the influence of structural changes on the antimicrobial potential of the hybrids. Antimicrobial test results showed that most of the synthesized hybrid compounds showed good activity with better results than the parent compounds. Molecular docking studies of the hybrids with the essential bacterial enzyme DHPS showed complexes with low binding energies, suggesting that DHPS could be a possible target for the antibacterial sulfonamide‐eugenol hybrids. Furthermore, most of the final compounds presented similar docking poses to that of the crystallographic ligand sulfamethoxazole. The results obtained allow us to conclude that these are promising compounds for use as new leads in the search for new antibacterial sulfonamides.

A series of structural analogs of aryl sulfonamide hybrid compounds were synthesised and their cytotoxic activity was evaluated against three human breast cancer cell lines (MCF‐7, MDA‐MB‐231 and Hs 578T). The compounds were designed through electronic, hydrophobic and steric modifications using the chemical structure of N‐{4‐[(2‐hydroxy‐3‐methoxy‐5‐propylphenyl)sulfamoyl]phenyl}acetamide (referred to as compound 7) as a starting point to then assess a structure‐activity relationship (SAR) study. From the data generated, we observed that compounds 9, 10 and 11 (which have modifications in the substituents of the aryl sulfonamide), efficiently reduced the cell viability of MCF‐7 and MDA‐MB‐231 cell cultures. Based on initial data, we selected compounds 10 and 11 for further investigations into their antiproliferative and/or cytotoxic profile against MDA‐MB‐231 cells, and we noted that compound 10 was the most promising compound in the series. Compound 10 promoted morphological changes and altered the dynamics of cell cycle progression in MDA‐MB‐231 cells, inducing arrest in G1/S transition. Taken together, these results show that the dihydroeugenol‐aryl‐sulfonamide hybrid compound 10 (which has an electron withdrawing nitro group) displays promising antiproliferative activity against MDA‐MB‐231 cell lines.