ABSTRACT
One-pot C-N/C-C bond formation of donor-acceptor cyclopropanes (DACs) with tetrahydroisoquinolines (THIQs) has been achieved to furnish benzo-fused indolizines. These reactions involve a MgI2-catalyzed ring opening of DACs and oxidative annulation using Mn(OAc)3·2H2O. The substrate scope and functional group diversity are the important practical features.
ABSTRACT
Sulfoxonium ylide chelation-assisted C-H allylation of arenes has been accomplished utilizing strained vinyl carbo/heterocycles as the allyl surrogates via sequential C-H and C-C/het bond activation. Broad substrate scope, Co-catalysis, selectivity, and late-stage drug mutation are the important practical features.
ABSTRACT
The site-selective C8-alkylation of quinolines has been accomplished using cyclopropyl alcohols as the alkylating agents and N-oxide as a weak chelating group in the presence of Co(III) catalysis via merging C-H/C-C bond activation. The use of cyclopropanol as the alkyl source, Co catalysis, substrate scope, HRMS analysis of the reaction intermediate, and late-stage mutation of drug molecules/natural products are the important practical features.
ABSTRACT
The Plasmodium FIKK kinases are diverged from human kinases structurally. They harbour conserved ATP-binding domains that are non-homologous to other existing kinases. FIKK9.1 kinase is considered as an essential protein for parasite survival. It is localized in major organelles present in parasite and trafficked throughout the infected RBC. It is speculated that FIKK9.1 may phosphorylate several substrates in the parasite's proteome and contribute to parasite survival. Therefore, FIKK9.1 is an attractive target that may lead to a novel class of antimalarials. To identify specific FIKK9.1 kinase inhibitors, we virtually screened organic structural scaffolds from a library of 623 entries. The top hits were identified based on conformations and molecular interactions with the ATP biophore. The hits were also validated under in vitro conditions. In this study, we identified seven top hit organic compounds that may arrest the growth of parasites by inhibiting FIKK9.1 kinase. Evaluation of top hit compounds in antimalarial activity assay identifies that the highly substituted 1,3-selenazolidin-2-imine 1 and thiophene 2 are inhibiting parasite growth with an IC50 of 3.2 ± 0.27 µg/ml and 3.13 ± 0.16 µg/ml, respectively. These functionalized heterocyclic compounds 1 and 2 kills the malaria parasite with an IC50 of 2.68 ± 0.02 µg/ml and 3.08 ± 0.14 µg/ml, respectively. Isothermal titration calorimetry analysis indicate that ATP is binding to the FIKK9.1 kinase. The dissociation constant (Kd) is measured to be 27.8 ± 2.07 µM with a stoichiometry of n = 1. The heterocyclic scaffolds 1 and 2 were abolishing the binding of ATP into the binding pocket. They in-turn reduce the ability of FIKK9.1 kinase to phosphorylate its substrate. Our study found that compounds 1 and 2 are potent inhibitor of FIKK9.1 kinase and the inhibition of FIKK9.1 kinase using small molecules disturbs the parasite life cycle and leads to the death of parasites. This provides new insight in development of novel antimalarials. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03677-x.
ABSTRACT
Pd-catalyzed annulative coupling of spirovinylcyclopropyl oxindoles with p-quinone methides has been accomplished via cascade carbon-carbon bond formation to afford bis-spirooxindole scaffolds. The mild reaction conditions, diastereoselectivity, functional group diversity, post-synthetic transformations, and mechanistic studies using DFT calculations are the important practical features.
ABSTRACT
Efficient annulation of in situ formed azaoxyallyl cations using a base has been accomplished with diaziridines to provide 1,2,4-triazines at room temperature. The substrate scope, scale up, functional group tolerance and transition-metal free reaction conditions are the important practical features.
Subject(s)
Triazines , CationsABSTRACT
Rh-catalyzed weak and traceless directing-group-assisted cascade C-H activation and annulation of sulfoxonium ylides with vinyl cyclopropanes as a coupling partner have been accomplished to furnish functionalized cyclopropane-fused tetralones at moderate temperature. The C-C bond formation, cyclopropanation, functional group tolerance, late-stage diversifications of drug molecules, and scale-up are the important practical features.
ABSTRACT
The Rh(III)-catalyzed C8-allylation of quinoline N-oxides has been accomplished using vinylcyclopropanes as an allyl source with excellent diastereoselectivity at room temperature. The C-H/C-C activation, substrate scope and natural product mutation are the important practical features.
ABSTRACT
The annulative coupling of donor-acceptor cyclopropanes with cyclic secondary amines is reported using the combination of Ni(OTf)2 and visible light assisted eosin Y catalysis for tandem C-N and C-C bond formation. The reaction sequence provides a potential synthetic tool for the construction of pyrrolotetrahydroisoquinolines.
Subject(s)
Cyclopropanes , Light , Amines/chemistry , Catalysis , Cyclopropanes/chemistry , Molecular StructureABSTRACT
Cobalt-catalyzed cascade C-N and C-O bond formation of epoxides with hydrazones is described to furnish oxadiazines using air as an oxidant. The catalyst plays a dual role as a Lewis acid followed by a redox catalyst to accomplish the C-H/O-H cyclization. Optically active styrene oxide can be reacted enantiospecifically (>99% ee).
Subject(s)
Cobalt , Hydrazones , Catalysis , Cobalt/chemistry , Epoxy Compounds , Oxides , StyrenesABSTRACT
Tandem C-N bond formation for the oxidative annulation of indolines with aziridines is accomplished employing the combination of DDQ and NaOCl at ambient conditions. Optically active aziridine can be coupled with high enantiomeric purity (>99% ee). The substrate scope, stereocontrol with the enantioenriched substrate, and scale-up are the important practical advantages.
