RESUMO
Compared with the widespread use of carbonylative Pd-catalyzed cross-coupling reactions, similar reactions involving isocyanide insertion are almost virgin territory. We investigated the intramolecular imidoylative cross-coupling of N-(2-bromoaryl)amidines, leading to 4-aminoquinazolines. After thorough optimization of the reaction with respect to palladium source and loading, ligand, base, temperature, and solvent, a small library of 4-aminoquinazolines was prepared to determine the scope of this method. Various substituents are tolerated on the amidine and the isocyanide, providing efficient access to a broad range of diversely substituted 4-aminoquinazolines of significant pharmaceutical interest.
RESUMO
Based on the indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. None of the bicyclic compounds was significantly active against the chloroquine-resistant strain Plasmodium falciparum K1, in contrast to the tricyclic derivatives. The tricyclic compound 2-methyl-2H-pyrido[3,4-b]indole (9), or 2-methyl-beta-carboline, showed the best in vitro activity, with an IC(50) value of 0.45 microM against P. falciparum K1, without apparent cytotoxicity against L6 cells (SI>1000). However, this compound was not active in the Plasmodium berghei mouse model. Structure-activity relationships are discussed and compared with related naturally occurring compounds.
Assuntos
Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Animais , Camundongos , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Indoloquinoline alkaloids represent an important class of antimalarial, antibacterial and antiviral compounds. They have been shown to bind to DNA via intercalation preferentially at GC-rich sequences containing nonalternating CC sites. The stability of complexes formed with biological macromolecules depends on noncovalent binding. In the present study, the ability of indoloquinolines to form intermolecular interactions with solvents was investigated by using NMR spectroscopy and density functional theory (DFT) (B3LYP/6-31G**) calculations. NMR data measured for indoloquinoline bases and the corresponding hydrochlorides are discussed in relation to the structure. DFT calculations of shielding constants in vacuo and in solution allowed the investigation of the influence of the environment on the NMR parameters. Calculations incorporating solvent effects indicated significant changes in the anisotropy of the electron distribution, reflected in the span of the chemical shielding tensor (Omega = sigma11 - sigma33). Solvent effects on the span of the 13C and 15N shielding tensor depended on the type of atom and the data indicated a significant influence of solute-solvent interactions.
Assuntos
Alcaloides/química , Indóis/química , Espectroscopia de Ressonância Magnética , Modelos Teóricos , Quinolinas/química , Solventes/química , Isótopos de Carbono , Isótopos de NitrogênioRESUMO
A series of chloro- and aminoalkylamino-substituted neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline) derivatives were synthesized and evaluated as antiplasmodial agents. The evaluation also included cytotoxicity (MRC5 cells), inhibition of beta-hematin formation, and DNA interactions (DNA-methyl green assay). Introduction of aminoalkylamino chains increased the antiplasmodial activity of the neocryptolepine core substantially. The most efficient compounds showed antiplasmodial activities in the nanomolar range. N(1),N(1)-Diethyl-N(4)-(5-methyl-5H-indolo[2,3-b]quinolin-8-yl)pentane-1,4-diamine 11c showed an IC(50) of 0.01 microM and a selectivity index of 1800.