Next-Generation Diarylurea Antibacterials: From Structural Design and Optimization to Microbial Target Specific Strategies

The global rise of multidrug-resistant (MDR) bacterial infections, particularly those caused by Staphylococcus aureus and Mycobacterium tuberculosis, has created an urgent need for novel antibacterial agents with innovative mechanisms of action. Among the promising candidates, diarylurea-based compounds have emerged as structurally versatile scaffolds with potent and broad-spectrum antimicrobial activity. This review highlights recent advances in the design, structure-activity relationships (SAR) investigations, and antimicrobial activity of diarylurea derivatives as antibacterial agents. It focuses on their activity against resistant Gram-positive and Gram-negative pathogens, especially methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis (Mtb). The review also explores the diverse mechanisms of action of these compounds, including inhibition of peptidoglycan synthesis, disruption of redox homeostasis, interference with membrane integrity, modulation of autolysin pathways, inhibition of DNA gyrase, and targeting of ATP synthase. Furthermore, structure–activity relationship (SAR) studies are discussed to elucidate the chemical features that enhance potency, selectivity, and metabolic stability. Taken together, the evidence surveyed in this review shows that diarylurea-based compounds are a promising scaffold for next-generation antibacterials. Their multifaceted modes of action and favorable pharmacological profiles position them as strong candidates in the fight against antimicrobial resistance. With repeated demonstrations of activity against resistant pathogens and the ability to circumvent conventional resistance pathways, this review provides a comprehensive overview of their potential and encourages further exploration of these scaffolds in antimicrobial drug discovery.