ABSTRACT
BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials.
Subject(s)
Anti-HIV Agents/pharmacology , Drug Discovery , HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , HIV/drug effects , Pyrimidines/pharmacology , Pyrimidinones/pharmacology , Thiazines/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Dose-Response Relationship, Drug , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/chemistry , Humans , Microbial Sensitivity Tests , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Structure-Activity Relationship , Thiazines/chemical synthesis , Thiazines/chemistryABSTRACT
Integration of viral DNA into the host cell genome is an obligatory process for successful replication of HIV-1. Integrase catalyzes the insertion of viral DNA into the target DNA and is a validated target for drug discovery. Herein, we report the synthesis, antiviral activity and pharmacokinetic profiles of several C2-carbon-linked heterocyclic pyrimidinone-4-carboxamides that inhibit the strand transfer step of the integration process.
Subject(s)
Amides/chemistry , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase/chemistry , HIV-1/enzymology , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacokinetics , HIV-1/drug effects , Half-Life , Heterocyclic Compounds/chemistry , Humans , Male , Pyrimidines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Ring-cleaved pleuromutilin derivatives comprised of a [5.3.1] bicyclic core structure have been synthesized and evaluated in vitro as antibacterial agents. Four of the compounds described were found to have MICsSubject(s)
Anti-Bacterial Agents/chemical synthesis
, Anti-Bacterial Agents/chemistry
, Anti-Bacterial Agents/pharmacology
, Diterpenes/chemical synthesis
, Diterpenes/chemistry
, Diterpenes/pharmacology
, Microbial Sensitivity Tests
, Polycyclic Compounds
, Staphylococcus aureus/drug effects
, Streptococcus pneumoniae/drug effects
, Structure-Activity Relationship
, Pleuromutilins
ABSTRACT
Stereoselective reduction of dehydroalanine double bond in nocathiacin I afforded the primary amide 2. Enzymatic hydrolysis of the amide 2 provided the carboxylic acid 3, which upon coupling with a variety of amines furnished amides 4-32. Some of these semi-synthetic derivatives have retained very good antibacterial activity and have improved aqueous solubility.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Enterococcus faecalis/drug effects , Peptides/chemical synthesis , Peptides/pharmacology , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Anti-Bacterial Agents/chemistry , In Vitro Techniques , Intercellular Signaling Peptides and Proteins , Microbial Sensitivity Tests , Molecular Structure , Peptides/chemistry , Solubility , Stereoisomerism , Structure-Activity Relationship , Water/chemistryABSTRACT
The synthesis and antibacterial activity of a series of nocathiacin I derivatives (4-20) containing polar water solubilizing groups is described. Thiol-Michael adducts containing acidic polar groups have reduced antibacterial activity whereas those with basic polar groups have retained very good antibacterial activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Peptides/chemical synthesis , Sulfhydryl Compounds/chemical synthesis , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Female , Intercellular Signaling Peptides and Proteins , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Peptides/administration & dosage , Peptides/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development , Sulfhydryl Compounds/pharmacologyABSTRACT
[reaction: see text] Alkyl/aryl amidoximes, prepared from the corresponding nitriles and N-alkylhydroxylamines, have readily undergone consecutive Michael additions to electron-deficient alkynes and provided highly substituted 1,2,4-oxadiazolines in good yields in homogeneous aqueous solution.
Subject(s)
Combinatorial Chemistry Techniques , Nitriles/chemistry , Oxadiazoles/chemical synthesis , Alkynes/chemical synthesis , Molecular Structure , Oximes/chemical synthesis , Solutions , Water/chemistryABSTRACT
Several nocathiacin I analogues (4-35) were synthesized and evaluated for their antibacterial activity. Most of these semi-synthetic analogues retained very good in vitro and in vivo antibacterial activity of 1.
Subject(s)
Anti-Bacterial Agents , Peptides , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Enterococcus faecalis/drug effects , Enterococcus faecalis/growth & development , Intercellular Signaling Peptides and Proteins , Microbial Sensitivity Tests , Molecular Structure , Peptides/chemical synthesis , Peptides/pharmacology , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/growth & development , Structure-Activity RelationshipABSTRACT
The synthesis and antibacterial activity of a series of new nocathiacin I derivatives (1-12) containing polar water solubilizing groups is described. Most of these compounds exhibited potent antibacterial activity and have improved water solubility. In addition, compounds 5, 7-9 also exhibited potent in vivo activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Peptides/chemical synthesis , Anti-Bacterial Agents/pharmacology , Enterococcus faecalis/drug effects , Intercellular Signaling Peptides and Proteins , Microbial Sensitivity Tests , Peptides/pharmacology , Solubility , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Structure-Activity Relationship , Water/chemistryABSTRACT
Several semi-synthetic bis- and mono-O-alkyl nocathiacin derivatives were synthesized and evaluated for antibacterial activity. Mono-O-alkyl N-hydroxyindole analogues 3a-l were prepared by regioselective alkylation. Bis-O-alkyl nocathiacins 4a-f were obtained by treatment with base and excess electrophile. A one-pot protection-alkylation-deprotection strategy was developed for the preparation of mono-O-alkyl hydroxypyridine analogues 5a,b. Most of the bis- and mono-O-alkyl nocathiacins maintained good in vitro activity but showed reduced in vivo efficacy when compared with the natural product. The excellent in vivo activity and improved water solubility of phosphate analogues 3m and 4g suggest their use as potential pro-drugs.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Peptides/chemical synthesis , Peptides/pharmacology , Alkylation/drug effects , Enterococcus faecalis/drug effects , Enterococcus faecalis/growth & development , Intercellular Signaling Peptides and Proteins , Microbial Sensitivity Tests/statistics & numerical data , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/growth & developmentABSTRACT
In water, the rate of Michael addition of amines and thiols to dehydroalanine amides was greatly accelerated, leading to shorter reaction times and higher yields. The scope of the new conditions was tested with a range of amines, thiols, and dehydroalanine amides. The ease and efficiency of this method provides an attractive route to the synthesis of natural and unnatural amino acid derivatives.
Subject(s)
Alanine/analogs & derivatives , Amides/chemistry , Amines/chemistry , Sulfhydryl Compounds/chemistry , Kinetics , Water/chemistryABSTRACT
A C-8 keto pleuromutilin derivative has been synthesized from the biotransformation product 8-hydroxy mutilin. A key step in the process was the selective oxidation at C-8 of 8-hydroxy mutilin using tetrapropylammonium perruthenate. The presence of the C-8 keto group precipitated interesting intramolecular chemistry to afford a compound (10) with a novel pleuromutilin-derived ring system.