Alkyl Chain Length as a Molecular Switch: From Supramolecular Reprogramming to Biointerface Modulation in α-Aminophosphonate Assemblies

Abstract

Alkyl chain length is typically viewed as a passive modulator of lipophilicity in drug-like molecules. Here, we demonstrate that it instead functions as a molecular switch that reprograms supramolecular organization, physicochemical behavior, and biological interface interactions in dialkyl-2-(((4-acetamidophenyl)amino)propan-2-yl)phosphonates. A comparative experimental-theoretical investigation was performed on diethyl (Compound I) and dibutyl (Compound II) derivatives using single-crystal and powder X-ray diffraction, DFT (ωB97X-D/6-31G*), DLS, NMR, IR/ATR, UV-Vis, fluorescence spectroscopy, HRMS, thermal analysis, QSAR, ADMET, and in vitro cytotoxicity studies. Crystallographic and computational analyses reveal that Compound I forms hydrogen-bond-stabilized dimers, whereas Compound II assembles into tetrameric architectures driven by cooperative (amine) N-H•••O=P and (amide) N-H•••O=C interactions. Dynamic light scattering confirms concentration-dependent nanoaggregation, while frontier molecular orbital analysis shows distinct electronic redistribution, increased polarizability, and enhanced electrophilicity for the tetramer. Despite dramatic differences in lipophilicity (consensus logP 1.57 vs. 11.29) and predicted solubility, both compounds exhibit low cytotoxicity (IC₅₀ > 100 μM), suggesting structural robustness with limited intrinsic antiproliferative activity. Integrated ADMET profiling indicates that alkyl elongation shifts the molecular transport paradigm from absorption-oriented behavior (Compound I) toward aggregationdriven, permeability-limited characteristics (Compound II). Collectively, the findings establish alkyl chain length not merely as a hydrophobic modifier but as a supramolecular control element that dictates assembly, electronic reactivity, and biological interaction pathways. This work provides a unified structure-aggregation-function framework for rational design of phosphonate-based molecular systems.