Although regular progress and improvement in the development of new anticancer sulfonamide derivatives is observed, according to Scopus data based on the last ten years (2024–2014) 1582 articles have been published on this topic, still the transition from preclinical to clinical trials for this group is challenging. Only three anticancer sulfonamides; pazopanib (malignant neoplasms of the kidney and soft tissue sarcoma), belinostat (peripheral T-cell lymphoma), and dabrafenib (unresectable and malignant melanoma) are available on the market [1,2].

The poor pharmacokinetic properties and high toxicity of drug candidates have been identified as significant limitations in the drug discovery process. Consequently, lipophilicity assessment represents a pivotal stage in the drug discovery pipeline, as it exerts a considerable influence on the diffusion of molecules through a biological membrane. Despite the detailed experimental protocols proposed by the OECD (tests no 107 and 117) and the numerous procedures developed for academic and industrial institutions, which describe methods for lipophilicity assessment based on the shake flask method or reversed-phase liquid chromatography (RP-LC), there are currently more bio-relevant approaches available, such as immobilized artificial membrane (IAM) chromatography. The IAM stationary phase has superior biomimetic properties compared to n-octanol/water measurements, as phosphatidylcholine molecules (the primary phospholipid of cell membranes) are covalently bound to silica, mimicking the phospholipid membrane monolayer [3] and recent studies have highlighted the differences between n-octanol/water partition and binding to phospholipids.

IAM-HPLC has been successfully applied to phospholipid affinity studies of several drug classes, including beta-blockers [4], calcium channel blockers [5], local anesthetics [6], biogenic amines [7], ipsapirone derivatives [8], and a number of structurally unrelated drugs. Moreover, IAM-HPLC has also been applied to the prediction of complex biological properties, including blood-brain barrier permeability [9], oral absorption [10], volume of distribution [11], skin permeation [12], and cardiotoxicity [12].

The main objective of the present study was to develop a QSRR model that can help to understand the molecular mechanism of binding of sulfonamides to phospholipids and support in silico prediction of this process. To achieve this goal, QSRR analysis was performed on a large and diverse set of sulfonamide derivatives synthesized in our laboratory, counting >500 molecules. In addition, the importance of the experimentally determined binding to phospholipids was verified in terms of its influence on anticancer activities measured in three cell lines, HCT-116, HeLa, and MCF-7.