Exploring the Chemical Space of Cephalosporins Across Generations
Henrique de Aguiar Mello, Itamar Luís Gonçalves · Drugs and Drug Candidates · 2026
Background/Objectives: Cephalosporins represent one of the most important classes of β-lactam antibiotics, widely used in clinical practice due to their broad-spectrum activity and favorable safety profile. As generations evolved, structural modifications were introduced to expand antimicrobial coverage and overcome β-lactamase resistance. This study aimed to analyze the drug-like properties of cephalosporins across different generations using molecular descriptors to identify structural and pharmacokinetic patterns influencing bioavailability and oral administration profiles. Methods: Thirty-eight cephalosporins representative of different generations were selected. Molecular data were obtained from PubChem, and SMILES were extracted and validated. Molecular descriptors (including MW, logP, TPSA, HBA, HBD, rotatable bonds, and global complexity indices) were calculated using the SwissADME and ChemDes platforms. Statistical analysis included ANOVA followed by post hoc tests, and principal component analysis (PCA). Results: A progressive increase in molecular weight, polarity, and TPSA was observed across generations, with fourth-generation cephalosporins showing significantly higher values compared to first-generation compounds (p < 0.0001). LogP decreased significantly in fourth-generation agents (p < 0.0001), reflecting increased polarity. PCA revealed that most compounds from generations 1–2 cluster in regions consistent with Lipinski’s and Veber’s rules, whereas fourth- and fifth generation - cephalosporins deviated substantially, prioritizing antimicrobial efficacy over oral bioavailability. Recurrent structural modifications such as oximes, tetrazoles, and aminothiazoles were identified, with increasing frequency in modern generations. Conclusions: The evolution of cephalosporins reflects a strategic shift toward enhanced antimicrobial potency and β-lactamase stability at the expense of oral bioavailability. Understanding these structural transitions provides valuable insights for rational drug design, aiming to balance antimicrobial effectiveness with favorable pharmacokinetic profiles essential for therapeutic success.