Abstract
Herein we describe the synthesis and evaluation of a series of novel 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-ones for in vitro cytotoxicity against three human cancer cell lines as well as for potential antimalarial activity against the chloroquine-sensitive strain 3D7 of Plasmodium falciparum. The title compounds were prepared via PdCl2-mediated endo-dig cyclization of 2-aryl-8-(arylethynyl)-6-bromo-2,3-dihydroquinazolin-4(1H)-ones. The latter were prepared, in turn, via initial Sonogashira cross-coupling of 2-amino-5-bromo-3-iodobenzamide with aryl acetylenes followed by boric acid-mediated cyclocondensation of the intermediate 2-amino-3-(arylethynyl)-5-bromobenzamides with benzaldehyde derivatives. The 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-ones 4a–k were evaluated for potential in vitro cytotoxicity against the breast (MCF-7), melanoma (B16) and endothelioma (sEnd.2) cell lines. All of the compounds except 4h and 4i were found to be inactive against the three cancer cell lines. Compound 4h substituted with a 4-methoxyphenyl and 4-fluorophenyl groups at the 3- and 5-positions was found to exhibit significant cytotoxicity against the three cancer cell lines. The presence of phenyl and 3-chlorophenyl groups at the 3- and 5-posiitons of the pyrroloquinazolinone 4i, on the other hand, resulted in significant cytotoxicity against vascular tumour endothelial cells (sEnd.2), but reduced activity against the melanoma (B16) and breast cancer (MCF-7) cells except at higher concentrations. The 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-ones 4a–l were found to be inactive against the chloroquine sensitive 3D7 strain of Plasmodium falciparum.
Highlights
The 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-ones 4a–l were found to be inactive against the chloroquine sensitive 3D7 strain of Plasmodium falciparum
4a–l for potential in vitro cytotoxicity against three cancer cell lines, cancer cell lines, namely, breast, melanoma and endothelioma cells. We evaluated these compounds namely, breast, melanoma and endothelioma cells. We evaluated these compounds for potential for potential antimalarial activity against the chloroquine-sensitive strain 3D7 of Plasmodium falciparum as described
We have demonstrated that the 2-amino-3-(arylalkynyl)-5-bromobenzamide framework represents an important synthon for the construction of novel 2,3-dihydro-1H-pyrroloquinazolin-1-ones via cyclocondensation and metal-assisted intramolecular C-N cyclization of the incipient 8-alkynylated quinazolinones
Summary
The design and synthesis of pyrroloquinazolinone-based compounds continue to attract considerable attention in synthetic organic chemistry due to their medicinal applications [1,2,3,4].The 3-alkyl substituted 7-phenyl-3H-pyrrolo[3,2-f ]quinazolin-9-ones and the 2,7-dihydro-1H-pyrrolo quinazolin-1-ones, for example, have been found to exhibit significant in vitro inhibitory activity in the micromolar range against tubulin polymerization and thrombin-induced aggregation, respectively [1].Both quinazolin-4(1H)-one and indole moieties are an integral part of the naturally occurring racemic pyrrolo[2,3-b]indolo[5,5-a,6-b,a]quinazolinone [(±)-cruciferane] A (Figure 1), which was first isolated from the roots of Isatis indigotic [2,5]. (−)-Phaitanthrin D and (+)-dihydropyrroloindoloquinazolinone depicted in Figure 1, on the other hand, were recently prepared from enantiomerically pure anthranilamide-based building blocks using HMDS/ZnCl2 and NaHMDS as reagents [3]. The 3-alkyl substituted 7-phenyl-3H-pyrrolo[3,2-f ]quinazolin-9-ones and the 2,7-dihydro-1H-pyrrolo quinazolin-1-ones, for example, have been found to exhibit significant in vitro inhibitory activity in the micromolar range against tubulin polymerization and thrombin-induced aggregation, respectively [1]. Both quinazolin-4(1H)-one and indole moieties are an integral part of the naturally occurring racemic pyrrolo[2,3-b]indolo[5,5-a,6-b,a]quinazolinone [(±)-cruciferane] A (Figure 1), which was first isolated from the roots of Isatis indigotic [2,5]. Several naturally occurring and synthetic have themselves have been themselves been found to exhibit interesting biological properties such anti-inflammatory, anticancer, found to exhibit interesting biological properties such anti-inflammatory, anticancer, anticonvulsant anticonvulsant and anti-hypertensive activities indole-based [6,7,8]. Compounds compounds exhibit pharmacological pharmacological properties such as antimicrobial, antimalarial, antioxidant and anti-tubercular properties such as antimicrobial, antimalarial, antioxidant and anti-tubercular activities, and this activities, and widely this moiety is widely distributed in numerous natural products [9,10]
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