ABSTRACT
This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.
Subject(s)
Antineoplastic Agents/chemistry , Benzimidazoles/chemistry , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Aurora Kinases , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacokinetics , Cell Line, Tumor , Humans , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
A new series of antimicrobial oxazolidinones bearing unsaturated heterocyclic C-rings is described. Dihydrothiopyran derivatives were prepared from the saturated tetrahydrothiopyran sulfoxides via a Pummerer-rearrangement/elimination sequence. Two new synthetic approaches to the dihydrothiazine ring system were explored, the first involving a novel trifluoroacetylative-detrifluoroacetylative Pummerer-type reaction sequence and the second involving direct dehydrogenation of tetrahydrothiopyran S,S-dioxide intermediates. Final analogs such as 4 and 13 represent oxidized congeners of recent pre-clinical and clinical oxazolidinones.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Anti-Bacterial Agents/chemistry , In Vitro Techniques , Microbial Sensitivity Tests , Molecular Structure , Oxazolidinones/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Combinatorial libraries of N-acylated 5-(S)-aminomethyloxazolidinone derivatives of S-oxide and S,S-dioxide tetrahydro-4(2H)-thiopyranyl and thiomorpholine phenyloxazolidinone series have been synthesized on a solid phase and evaluated for antimicrobial activity. Several novel potent leads have been identified, including orally active oxazolidinones with enhanced activity against respiratory tract infection pathogens Haemophilus influenzae and Moraxella catarrhalis.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Haemophilus influenzae/drug effects , Moraxella catarrhalis/drug effects , Morpholines/chemistry , Oxazolidinones/pharmacokinetics , Oxides/chemistry , Oxygen Compounds/pharmacokinetics , Animals , Anti-Bacterial Agents/administration & dosage , Biological Availability , Combinatorial Chemistry Techniques , Haemophilus Infections/microbiology , Lipid Metabolism , Male , Microbial Sensitivity Tests , Moraxellaceae Infections/microbiology , Oxazolidinones/administration & dosage , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Thiazole peptide GE2270 A (1) possesses potent antimicrobial activity against many gram-positive pathogens, including methicillin resistant Staphylococcus aureus (S. aureus, MRSA; MIC(90)=0.06 microg/mL) and vancomycin resistant Enterococcus spp. (VRE; MIC(90)=0.03 microg/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.