Combinatorial modification of natural products:: Synthesis and in vitro analysis of derivatives of thiazole peptide antibiotic GE2270 A:: A-ring modifications

Thiazole peptide GE2270 A (1) possesses potent antimicrobial activity against many gram-positive pathogens, including methicillin resistant Staphylococcus aureus (S. aureus, MRSA; MIC90=0.06 mug/mL) and vancomycin resistant Enterococcus spp. (VRE; MIC90=0.03 mug/mL); however its poor aqueous solubility has prohibited its development for the clinical treatment of infections. An integrated combinatorial and medicinal chemistry program was employed to identify derivatives of 1 that retain activity but possess greatly enhanced aqueous solubility. (C) 2003 Elsevier Ltd. All rights reserved.