ABSTRACT
An efficient approach for the synthesis of indole- and pyrrole-fused diketopiperazines has been developed. This protocol involves the Ugi four-component reaction (U-4CR) followed by an intramolecular cyclization of the Ugi products at room temperature to afford the desired products in good to excellent yields. In addition, it is interesting to report the subsequent regioselective ring-opening of diketopiperazine unit occurring via an intermolecular transamidation reaction under mild condition, resulting in the formation of highly functionalized indole-2-carboxamides and pyrrole-2-carboxamides.
Subject(s)
Diketopiperazines/chemistry , Indoles/chemistry , Indoles/chemical synthesis , Pyrroles/chemistry , Pyrroles/chemical synthesis , Cyclization , Molecular Structure , StereoisomerismABSTRACT
A novel ligand-free palladium-catalyzed cascade reaction for the synthesis of highly diverse isoquinolin-1(2H)-one derivatives from isocyanide and amide precursors synthesized by Ugi-MCR has been developed. A broad variety of acids, amines, and isocyanides were used as starting materials for Ugi-MCR leading to various amide precursors, which in turn provided entry into diverse isoquinolin-1(2H)-one derivatives. The reaction proceeds through tandem isocyanide insertion with intramolecular cyclization followed by a Mazurciewitcz-Ganesan type sequence to provide isoquinoline-1(2H)-one derivatives in moderate to good yields.
Subject(s)
Amides/chemistry , Cyanides/chemistry , Isoquinolines/chemistry , Palladium/chemistry , Amides/chemical synthesis , Catalysis , Cyclization , Ligands , Models, Molecular , Molecular StructureABSTRACT
A series of novel keto-enamine chalcone-chloroquine based hybrids were synthesized following new methodology developed in our laboratory. The synthesized compounds were screened against chloroquine sensitive strain (3D7) of Plasmodium falciparum in an in vitro model. Some of the compounds were showing comparable antimalarial activity at par with chloroquine. Compounds with significant in vitro antimalarial activity were then evaluated for their in vivo efficacy in Swiss mice against Plasmodium yoelii (chloroquine resistant N-67 strain), wherein compounds 25 and 27 each showed an in vivo suppression of 99.9% parasitaemia on day 4. Biochemical studies reveal that inhibition of hemozoin formation is the primary mechanism of action of these analogues.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Biphenyl Compounds/chemistry , Chalcone/chemistry , Chloroquine/chemistry , Imidazoles/chemistry , Plasmodium falciparum/drug effects , Plasmodium yoelii/drug effects , Administration, Oral , Animals , Cell Line , Chlorocebus aethiops , Chloroquinolinols/chemistry , Chloroquinolinols/pharmacology , Chloroquinolinols/therapeutic use , Cyclohexenes/chemistry , Cyclohexenes/pharmacology , Cyclohexenes/therapeutic use , Drug Resistance , Malaria/drug therapy , Mice , Vero CellsABSTRACT
Several diversity-oriented syntheses of N-fused polycyclic heterocycles have been demonstrated but most of them are based on point diversity within the same library and usually involve time-consuming sequential multistep syntheses, which also suffer from low yields and/or poor precursor scopes. We have developed a new strategy for the syntheses of skeletal diverse N-fused polycyclic compounds via an Ugi-type MCR followed by a CuI-catalyzed coupling reaction or tandem Pictet-Spengler reaction. This two-step sequence provides eight distinct skeleton of fused {6-5-5-6}, {5-5-5-6}, {6-5-6-6}, and {5-5-6-6} ring systems that have applications in medicinal chemistry and chemical genetics too.
