Synthesis of pyrimido[5,4-c]quinolines and related quinolines as potential antimalarials

Abstract

3-Ethylaminomethyl-2-methyl-4(1H)-quinolone (1a) and its 6-CH3, 6-OCH3, and 7-Cl derivatives were prepared by means of the Mannich reaction. Conversion to the 4-chloro derivatives and condensation with 3-chloroaniline gave the corresponding 4-(3-chloroanilino) derivatives. Cyclization of 4-(3-chloroanilino)-2,6-dimethyl-3-ethyl-aminomethylquinoline (3a) and its 6-OCH3 derivative with paraformaldehyde gave 1-(3-chlorophenyl)-3,9-dimethyl-3-ethyltetrahydropyrimido[5,4-c]quinoline (4a) and the 9-OCH3 derivative 4b. Treatment of 4b with benzaldehyde gave 1-(3-chlorophenyl)-3-ethyl-9-methoxy-5-styryltetrahydropyrimido[5,4-c]quinoline (5). 3-Benzylaminomethyl-6-methoxy-2-methyl-4(1H)-quinolone (1e) and 3,3'-(1,3-benzyliminodimethylene)di[2-methyl-4(1H)-quinolone] (6b) were also synthesized. The compounds were inactive as antimalarials.

Pyrimido[5,4‐c]quinolines: Synthesis from 3,4‐Di‐functionallized Quinoline, Reactivity and Biological Activities

“…[50] 2.10. From 3-aminomethyl-4-aminoquinolin-4(3H)-one Nasr and collaborators [13] synthesized 3-ethylaminomethyl-2methyl-4(1H)-quinolone 240a,b and its derivatives through a Mannich reaction utilizing 2-methyl-4-quinolone derivatives 239a,b, [51] Despite their structural diversity, the compounds were found to be inactive as antimalarials (Scheme 34). [13] When 1-acetylbenzotriazole 247 is heated with an excess of C 6 H 5 -NCO or p-MeC 6 H 4 NCO 18 in a sealed tube at 210 °C for 24 h, it leads to the formation of pyrimidino [5,4-c]…”

“…The pyrimido [5,4-c]quinoline nucleus (PyQ5,4-c) constitutes a key structural element in numerous biologically active organic compounds, showcasing a diverse array of pharmacological activities. These compounds have demonstrated efficacy in areas such as anti-bacterial, [9] anti-cancer, [10][11][12] anti-malarial, [13] and anti-oxidant [14] activities. Furthermore, certain PyQ5,4-c derivatives have been identified as inhibitors of Na + /H + Saif was awarded his bachelor's degree in chemistry from Taif University in 2013.…”

“…into the synthesis of PyQs5,4-c from (thio)barbituric acid and their analogs, [5] and considering the recent advancements in both synthetic chemistry and the understanding of the biological activities of PyQs4,5-b, [6,7] this comprehensive review offers a systematic and in-depth exploration of the chemical reactivity and preparation processes associated with PyQs5,4-c. By amalgamating insights from various disciplines, this review aims to contribute to the broader understanding and potential applications of PyQs5,4-c in both the realms of synthetic chemistry and biological activities. Moreover, pyrimido [5,4c]quinoline nucleus (PyQ5,4-c) is present in several biologically active organic compounds, which exhibit, anti-bacterial, [9] anticancer, [10][11][12] anti-malarial, [13] and anti-oxidant [14] activity. Furthermore, some PyQ5,4-c reported as Na + /H + Exchanger-1 Inhibitory, [15] and as potent 5-HT1 A/2 A and 5-HT7 receptor ligands.…”

Synthesis and structure elucidation of five new pyrimido[5,4‐c]quinoline‐4(3H)‐one derivatives using 1D and 2D NMR spectroscopy

“…Pyrimidoquinoline nuclei have been of appeal to organic, medicinal and materials scientists over many years due to their extremely varied biological activities such as antimalarial,2 antimi‐crobial,3–6 analgesic,5–8 anti‐inflammatory,5–8 antioxidant,6, 8, 9 antifungal,10 antitumor,11–14 and antiviral 15. Recently, attention has been focused on the synthesis and bioactivities of pyrimido[5,4‐ c ]quinoline derivatives 9, 16–20. Moreover, previous researches have shown that they exhibited several pharmacological activities (e.g.…”

“…Moreover, previous researches have shown that they exhibited several pharmacological activities (e.g. antioxidant,9 antimalarials,19 antiherpetic20). Nevertheless, these derivatives suffered from serious limitations such as the rapid development of drug resistance.…”