Bacterial resistance to antibiotics remains an imposing global public health challenge. Of the most serious pathogens, methicillin-resistant Staphylococcus aureus (MRSA) is problematic given strains have emerged that exhibit resistance to several antibiotic classes including β-lactams and agents of last resort such as vancomycin. New antibacterial agents composed of unique chemical scaffolds are needed to counter this public health challenge. The present study examines two synthetic diphenylurea compounds 1 and 2 that inhibit growth of clinically-relevant isolates of MRSA at concentrations as low as 4 µg/mL and are non-toxic to human colorectal cells at concentrations up to 128 μg/mL. Both compounds exhibit rapid bactericidal activity, completely eliminating a high inoculum of MRSA within four hours. MRSA mutants exhibiting resistance to 1 and 2 could not be isolated, indicating a low likelihood of rapid resistance emerging to these compounds. Bacterial cytological profiling revealed the diphenylureas exert their antibacterial activity by targeting bacterial cell wall synthesis. Both compounds demonstrate the ability to resensitize vancomycin-resistant Staphylococcus aureus to the effect of vancomycin. The present study lays the foundation for further investigation and development of diphenylurea compounds as a new class of antibacterial agents.

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Exploring the structure–activity relationships (SAR) of a new set of phenylpyrazoles unveiled a potential anti‐enterococcus lead compound 12. The benzofuran moiety linked to the phenylpyrazole 12 was 32 times better than vancomycin against Enterococcus faecalis ATCC 51299. Besides, compound 12 is expected to have an excellent oral bioavailability according to the in silico studies. Of SAR analysis, we found that the benzofuran side chain was essential for the activity. Changing the benzofuran with either benzothiophene, phenyl, pyridinyl, tolyl, or naphthyl reduces/nullifies the pharmacological action. Besides the anti‐enterococcal activity, derivatives 4 and 6 can be used to develop new broad‐spectrum antibiotics as they exhibited activity against the wild‐type highly virulent Escherichia coli isolate. Moreover, compound 13 was proved to show antifungal activity (MIC = 4 μg/ml) against the Candida albicans SS5314 (wild type). Finally, the in silico analysis showed that those compounds have good profiles regarding the absorption, distribution, metabolism, and excretion studies, drug‐likeness and pharmacokinetics properties.

The current arsenal of antimicrobials couldn't hold back the rapid and ferocious growth of the antimicrobial resistance phenomenon. Collectively the current situation points to the pressing need to develop other effective antimicrobial agents.In the search for novel antimicrobials, phenylthiazole derivatives have recently been found to possess antibacterial activity particularly against a range of several antibiotic-resistant staphylococcus aureus strains. Modification of the nitrogenous head by incorporation the hydrolysable -HC=N-linkage within a pyrimidine ring bearing one or more hydrogen bond-promoting group led to the discovery of the second generation of phenylthiazoles, with more potent activity and longer half-lives compared to the lead compound 1a.Based on the above rationale, the objective of this study was to create a new set of structures of n-butylphenylthiazole-5-pyrimidine that contains two or more heteroatoms in their side chain and to study the relationship between the structural form of these compounds and their antimicrobial activity and spectrum against certain multi-drug resistance (MDR) strains. The new set of derivatives is designed to cover all the possibilities of side chains carbon-units distance and spatial configurations.