ABSTRACT
FimH is a type I fimbrial lectin located at the tip of type-1 pili of Gram-negative uropathogenic Escherichia coli (UPEC) guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small molecule inhibitor is considered as a promising new therapeutic alternative to treat urinary tract infections caused by UPEC. Herein, we report that compounds having the S-glycosidic bond (thiomannosides) had improved metabolic stability and plasma exposures when dosed orally. Especially compound 5h showed the potential to inhibit biofilm formation and also to disrupt the preformed biofilm. And compound 5h showed prophylactic effect in UTI model in mice.
Subject(s)
Fimbriae Proteins/antagonists & inhibitors , Mannosides/pharmacology , Urinary Tract Infections/drug therapy , Adhesins, Escherichia coli/metabolism , Administration, Oral , Animals , Biofilms/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Fimbriae Proteins/metabolism , Mannosides/administration & dosage , Mannosides/chemistry , Mice , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , Urinary Tract Infections/urineABSTRACT
Gram-positive bacteria are among the most common human pathogens associated with clinical infections which range from mild skin infections to sepsis. Resistance towards existing class of drugs by Gram-positive bacteria including methicillin resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis (MRSE) and vancomycin resistant enterococci (VRE) is a growing concern. There is an urgent need to discover new antibiotics which are active against resistant strains of Gram positive bacteria. We report herein a novel class of spiropyrimidinetrione oxazolidinone derivatives as novel antibacterial agents. Key step towards the synthesis of title compounds involved the use of tert-amino reaction with [1,5]-hydride shift leading to the new CC bond formation. Compound 30n has demonstrated potent antibacterial activity against a panel of Gram-positive microbial strains including MRSA, MRSE, and LNZ and vancomycin resistant strains of E. faecalis. Further, molecular docking studies suggest that 30n has binding mode similar to that of LNZ in 50S RNA ribosome.
Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Design , Oxazolidinones/pharmacology , Pyrimidinones/pharmacology , Spiro Compounds/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Staphylococcus epidermidis/drug effects , Structure-Activity Relationship , Vancomycin-Resistant Enterococci/drug effectsABSTRACT
Designing drug candidates exhibiting polypharmacology is one of the strategies adopted by medicinal chemists to address multifactorial diseases. Metabolic disease is one such multifactorial disorder characterized by hyperglycaemia, hypertension and dyslipidaemia among others. In this paper we report a new class of molecular framework combining the pharmacophoric features of DPP4 inhibitors with those of ACE inhibitors to afford potent dual inhibitors of DPP4 and ACE.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Metabolic Syndrome/drug therapy , Angiotensin-Converting Enzyme Inhibitors/chemistry , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dogs , Humans , Inhibitory Concentration 50 , Mice , Microsomes, Liver/drug effects , Molecular Docking Simulation , RatsABSTRACT
The induction of conformationally restricted N-(aryl or heteroaryl)-3-azabicyclo[3.1.0]hexane derivatives at P(2) region of compounds of 2-cyanopyrrolidine class was explored to develop novel DPP-IV inhibitors. The synthesis, structure-activity relationship, and selectivity against related proteases are delineated.