ABSTRACT
The emergence of multidrug-resistant strains of Mycobacterium tuberculosis and resistance to current anti-TB drugs call for the discovery and development of new effective anti-TB drugs. TMC207 is the lead candidate of a novel class of antimycobacterial agents, the diarylquinolines, which specifically inhibit mycobacterial ATP synthase and displays high activity against both drug-susceptible and multidrug-resistant strains of Mycobacterium tuberculosis. This article covers both synthesis pathways as well as qualitative and quantitative analyses of the structure-activity relationships of the diarylquinoline series on Mycobacterium smegmatis activity.
Subject(s)
Antitubercular Agents/chemical synthesis , Drug Discovery/methods , Quinolines/chemical synthesis , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Antitubercular Agents/toxicity , Cell Survival/drug effects , Chemistry, Pharmaceutical , Diarylquinolines , Drug Resistance, Multiple, Bacterial , HeLa Cells , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Mycobacterium smegmatis/drug effects , Mycobacterium smegmatis/growth & development , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/growth & development , Quantitative Structure-Activity Relationship , Quinolines/chemistry , Quinolines/pharmacology , Quinolines/toxicityABSTRACT
Based on the structure of R115777 (tipifarnib, Zarnestra), a series of farnesyltransferase inhibitors have been synthesized by modification of the 2-quinolinone motif and transposition of the 4-chlorophenyl ring to the imidazole or its replacement by 5-membered rings. This has yielded a novel series of potent farnesyltransferase inhibitors.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase/antagonists & inhibitors , Quinolones/pharmacology , Antineoplastic Agents/chemistry , Enzyme Inhibitors/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Quinolones/chemistryABSTRACT
Replacement of the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA series by a 4-methyl-1,2,4-triazol-3-yl group gave us compounds with similar structure-activity relationship profiles showing that this triazole is potentially a good surrogate to imidazole for farnesyltransferase inhibition.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Quinolones/chemical synthesis , Quinolones/pharmacology , Triazoles/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Division/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Kinetics , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Molecular Conformation , Quinolones/administration & dosage , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
A series of (4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)azoloquinolines and -quinazolines was prepared. These compounds displayed potent Farnesyl Protein Transferase inhibitory activity and tetrazolo[1,5-a]quinazolines are promising agents for oral in vivo inhibition.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , Cell Division/drug effects , Drug Design , Enzyme Inhibitors/chemical synthesis , Farnesyltranstransferase , Kinetics , Molecular Conformation , Molecular Structure , Quinolones/chemical synthesis , Quinolones/pharmacology , Structure-Activity RelationshipABSTRACT
The evaluation of structure-activity relationships associated with the modification of the R115777 quinolinone ring moiety displaying potent in vitro inhibiting activity is described.
