Quinolone analogs 11: Synthesis of novel 4‐quinolone‐3‐carbohydrazide derivatives with antimalarial activity

Abstract

The reaction of the 6-substituted 1-methyl-4-quinolone-3-carboxylates 10a,b with hydrazine hydrate gave the 3-carbohydrazides 7a,b, respectively, whose reaction with 2-, 3-, and 4-pyridinecarbaldehydes afforded the 3-(N 2 -pyridylmethylene)carbohydrazides 8a-c and 9a-c. The Curtius rearrangement of compound 7b provided the N,N 0 -bis(4-quinolon-3-yl)urea 14 presumably via the 3-carboazide 11 and then 3-isocyanate 12. Compounds 7a, 8a, and 9a were found to possess antimalarial activity from the in vitro screening data.

Quinolone Analogues 15: Synthesis and Antimalarial Activity of 4‐Phenyl‐1‐(1‐triazolylmethyl‐4‐quinolon‐3‐ylcarbonyl)semicarbazide and Related Compounds

“…The in vitro antimalarial activity to chloroquine‐resistant P . falciparum (Gambia Cl D‐3 strain, ATCC 50037) was studied for new compounds according to a method described in previous articles . The 4‐phenyl‐1‐(1‐triazolylmethyl‐4‐quinolon‐3‐ylcarbonyl)(thio)semicarbazides 6a and 6b represented the antimalarial activity in concentration of 3.89 and 3.91 μM (IC 50 ), respectively, wherein the IC 50 of chloroquine as a reference was 0.22 μM.…”

“…In previous articles, we also reported the synthesis of the antimalarial 1‐(pyridin‐4‐ylalkenyl)‐4‐quinolone‐3‐carboxylate ( 1 ) , 1‐methyl‐4‐quinolone‐3‐[ N 2 ‐(pyridin‐2‐ylmethylene)]carbohydrazides ( 2 ) , and 1‐aryl‐3‐(4‐quinolon‐2‐yl)ureas ( 3 ) (Chart ). The 4‐quinolone ring and urea moiety of the 1‐aryl‐3‐(4‐quinolon‐2‐yl)ureas ( 3 ) were requisite for the antimalarial activity to Plasmodium falciparum , because the 1‐aryl‐3‐(4‐methoxyquinolin‐2‐yl)ureas ( 4 ) showed no antimalarial activity to P .…”

Quinolone Analogs 14: Synthesis of Antimalarial 1‐Aryl‐3‐(4‐quinolon‐2‐yl)ureas and Related Compounds

“…The reaction of compound 6a (Scheme ) or 6b (Scheme ) with nitrous acid gave the 4‐quinolone‐2‐carbonylazide 7a or 4‐methoxyquinoline‐2‐carbonylazide 7b , whose reaction with aniline derivatives afforded the 1‐aryl‐3‐(4‐quinolon‐2‐yl)ureas 5a , 5b , 5c , 5d , 5e and 1‐aryl‐3‐(4‐methoxyquinolin‐2‐yl)ureas 11a , 11b , 11c , 11d presumably via an isocyanate intermediate 8a or 8b , respectively. The reaction of compound 7a or 7b with arylaminoacetamide or arylaminoacetate provided the 1‐aryl‐3‐(4‐quinolon‐2‐yl)imidazolidine‐2,4‐diones 9a , 9b or 1‐aryl‐3‐(4‐methoxyquinolin‐2‐yl)imidazolidine‐2,4‐diones 12a , 12b , respectively, presumably via an intermediate shown in Chart .…”

“…The in vitro antimalarial activity to chloroquine‐resistant P. falciparum (Gambia Cl D‐3, ATCC‐50037) was investigated for novel compounds 5 and 9 , 10 , 11 , 12 , 13 according to a method described in the previous papers . The screening data are shown in Table , wherein the IC 50 values are expressed in micromolar (μM) concentration.…”

“…Recently, we also reported the synthesis of the antimalarial 1‐(pyridin‐4‐ylalkenyl)‐4‐quinolone‐3‐carboxylate 3 and 1‐methyl‐4‐quinolone‐3‐[ N 2 ‐(pyridin‐2‐ylmethylene)]carbohydrazides 4 (Chart ) in the course of the study on structural modification of ordinary antibacterial new quinolones, which were also known as the antimalarial agent [IC 50 (below 10 µg/mL in ciprofloxacin)] . In continuation of the previous works, we synthesized 1‐aryl‐3‐(4‐quinolon‐2‐yl)ureas 5 in the present investigation, and some of compounds 5 were found to exhibit antimalarial activity better than compounds 3 and 4 , which would be due to the presence of urea moiety in compound 5 .…”