ABSTRACT
A conceptually new and straightforward introduction of sulfonyl groups at the C-7 position of an indole ring has been achieved via AlCl(3) mediated unexpected regioselective sulfonyl group migration for N-alkyl/aryl/heteroarylsulfonyl indoles affording potential inhibitors of Mycobacterium tuberculosis H37Rv chorismate mutase.
Subject(s)
Aluminum Compounds/chemistry , Chlorides/chemistry , Chorismate Mutase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Mycobacterium tuberculosis/enzymology , Sulfones/chemistry , Aluminum Chloride , Chorismate Mutase/metabolism , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of novel N-aryl substituted thieno[2,3-d]pyrimidin-4(3H)-ones were designed and synthesized as potential inhibitors of chorismate mutase. Synthesis of this class of compounds was carried out by using Cu-mediated C-N bond forming reaction between thieno[2,3-d]pyrimidin-4(3H)-ones and aryl boronic acids. The reaction can be performed in an open flask as the conversion was found to be not sensitive to the presence of air or atmospheric moisture. A range of compounds were prepared by using this method and single crystal X-ray diffraction study was performed using a representative compound. In vitro pharmacological data of some of the compounds synthesized along with dose response studies using active molecules are presented. In silico interactions of these molecules with chorismate mutase are also presented.
Subject(s)
Chorismate Mutase/antagonists & inhibitors , Copper/chemistry , Enzyme Inhibitors/pharmacology , Organometallic Compounds/chemistry , Pyrimidinones/pharmacology , Catalysis , Chorismate Mutase/genetics , Chorismate Mutase/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Models, Molecular , Molecular Structure , Mycobacterium tuberculosis/enzymology , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Structure-Activity RelationshipABSTRACT
A direct and single-step method has been developed for the synthesis of mono and 2,3-disubstituted quinoxalines by using a AlCl(3) induced (hetero)arylation of 2,3-dichloroquinoxaline. Both symmetrical and unsymmetrical 2,3-disubstituted quinoxalines can be prepared conveniently by using this method under appropriate reaction conditions. The reaction proceeds via C-C bond formation and can be utilized for the preparation of a variety of quinoxaline derivatives from readily available starting materials and reagents. The molecular structure of a representative compound was confirmed by single crystal X-ray diffraction study. Some of the compounds synthesized were tested for chorismate mutase inhibitory properties in vitro and one compound showed promising activity representing one of the few examples of chorismate mutase inhibition by a heteroarene based small molecule.
Subject(s)
Aluminum Compounds/chemistry , Antitubercular Agents/chemical synthesis , Chlorides/chemistry , Quinoxalines/chemical synthesis , Aluminum Chloride , Crystallography, X-Ray , Models, Molecular , Molecular Structure , Quinoxalines/pharmacologyABSTRACT
A rapid and direct access to N-aryl substituted fused triazinone derivatives has been accomplished via N-arylation of 1,2,3-triazin-4-one ring involving a Cu-mediated coupling between triazinone derivatives and aryl boronic acids. A combination of Cu(OAc)(2)-Et(3)N in 1,2-dichloroethane was found to be effective and various fused triazinone derivatives have been prepared by using this methodology. Molecular structure of a representative compound was confirmed by single crystal X-ray diffraction study. The scope and limitations of this reaction is discussed. Some of the compounds synthesized were tested for chorismate mutase inhibitory properties in vitro. The in vitro dose response study of an active compound is presented.
Subject(s)
Chorismate Mutase/antagonists & inhibitors , Copper/chemistry , Enzyme Inhibitors/pharmacology , Organometallic Compounds/chemistry , Triazines/pharmacology , Catalysis , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Triazines/chemical synthesis , Triazines/chemistryABSTRACT
A multi component based synthesis involving palladium catalyzed C-C bond forming reaction has been developed as a new strategy to access systematically modified functionalized 2-aminochromenes. This MCR involves the use of bromobenzaldehyde as a key component and is highlighted by generating a new compound library. Many of these compounds showed Mycobacterium tuberculosis H37Rv chorismate mutase inhibiting properties in vitro representing the lead example of chorismate mutase inhibition by heteroarene based compounds.
