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    Evaluation of N-phenyl-2-aminothiazoles for treatment of multi-drug resistant and intracellular Staphylococcus aureus infections
    (Elsevier Masson SAS, 9/15/2020) Shahin, Inas G.; Abutaleb, Nader S.; Alhashimi, Marwa; .Kassab, Asmaa E; Mohamed, Khaled O; Taher, Azza T; Seleem, Mohamed N; Mayhoub, Abdelrahman S.
    European Journal of Medicinal Chemistry Volume 202, 15 September 2020, 112497 Research paper Evaluation of N-phenyl-2-aminothiazoles for treatment of multi-drug resistant and intracellular Staphylococcus aureus infections Author links open overlay panelInas G.Shahina1Nader S.Abutalebb1MarwaAlhashimibAsmaa E.KassabcKhaled O.MohamedcAzza T.TahercdMohamed N.SeleembeAbdelrahman S.Mayhoubfg a Organic Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts, Giza, 11787, Egypt b Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, 47907, USA c Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt d Department of Pharmaceutical Organic Chemistry, College of Pharmacy, October 6 University, 6-October, Giza, Egypt e Purdue Institute of Inflammation, Immunology, and Infectious Disease, West Lafayette, IN, 47907, USA f Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al- Azhar University, Cairo, 11884, Egypt g University of Science and Technology, Nanoscience Program, Zewail City of Science and Technology, October Gardens, 6th October, Giza, 12578, Egypt Received 9 December 2019, Revised 16 February 2020, Accepted 19 May 2020, Available online 25 June 2020. crossmark-logo https://doi.org/10.1016/j.ejmech.2020.112497 Get rights and content Highlights • N-Phenyl-2-aminothiazoles was defined as a potent scaffold for beating MDR-pathogens. • Aminoguanidine is an essential structural element for antimicrobial activity. • The most potent derivatives were active against linezolid and vancomycin-resistant staphylococci/enterococci. • 3e reduced the intracellular pathogen population by about 99%. • 3e displayed metabolic stability when subjected to human liver microsomes. Abstract The increasing emergence of antibiotic-resistant bacterial pathogens calls for additional urgency in the development of new antibacterial candidates. N-Phenyl-2-aminothiazoles are promising candidates that possess potent anti-MRSA activity and could potentially replenish the MRSA antibiotic pipeline. The initial screen of a series of compounds in this novel class against several bacterial strains revealed that the aminoguanidine analogues possessed promising activities and superior safety profiles. The determined MICs of these compounds were comparable to, if not better than, those of the control drugs (linezolid and vancomycin). Remarkably, compounds 3a, 3b, and 3e possessed potent activities against multidrug resistant staphylococcal isolates and several clinically important pathogens, such as vancomycin-resistant enterococci (VRE) and Streptococcus pneumoniae. In addition, the compounds were superior to vancomycin in the rapid killing of MRSA and the longer post-antibiotic effects. Furthermore, low concentrations of compounds 3a, 3b, and 3e reduced the intracellular burden of MRSA by greater than 90%. Initial in vitro PK/toxicity assessments revealed that compound 3e was highly tolerable and possessed a low metabolic clearance rate and a highly acceptable half-life.