Pyrimidine-based hybrids as modulators of P-glycoprotein-mediated multidrug resistance: lipophilicity and SAR perspectives

An important obstacle to efficient anticancer therapy is multidrug resistance (MDR) mediated by efflux transporters, particularly P-glycoprotein (P-gp/ABCB1). Pyrimidine-based hybrids comprise different scaffolds with favorable physicochemical profiles that can modulate transporter activity. This review presents a descriptor-oriented analysis of the lipophilicity, polarity, amphiphilicity, and conformational flexibility across the principal structural architectures of pyrimidine hybrids (linked, fused, and natural product-derived), with conjugation considered as a cross-cutting structural feature to assess their influence on membrane permeability, intracellular accumulation, and P-gp modulation.Particular emphasis is placed on integrating experimentally determined and computationally predicted lipophilicity descriptors with structure-activity relationships (SAR) to demonstrate how scaffold architecture and physicochemical properties collectively influence MDR-related biological responses.This relationship is illustrated by studies on pyrimidine-hydrazone, pyrazolo[3,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, and artesunate-pyrimidine hybrids, which collectively demonstrate that balanced lipophilicity and amphiphilicity are key determinants of P-gp modulation.Collectively, SAR analyses, molecular docking, molecular dynamics simulations, and experimental studies indicate that hydrophobic and amphiphilic balance, rather than hydrogen-bonding capacity alone, govern P-gp recognition. By integrating structural, physicochemical, and biological findings, this review provides a framework for the rational optimization of pyrimidine-based hybrids to achieve more effective P-gp modulation and improved anticancer drug design.