ABSTRACT
Hypoxic pulmonary vasoconstriction (HPV), a unique response of pulmonary circulation, is critical to prevent hypoxemia under local hypoventilation. Hypoxic inhibition of K+ channel is known as an important O2-sensing mechanism in HPV. Carbon monoxide (CO) is suggested as a positive regulator of Ca2+-activated K+ channel (BK(Ca)), a stimulator of guanylate cyclase, and an O2-mimetic agent in heme moiety-dependent O2 sensing mechanisms. Here we compared the effects of CO on the HPV (Po2, 3%) in isolated pulmonary artery (HPV(PA)) and in blood-perfused/ventilated lungs (HPV(lung)) of rats. A pretreatment with CO (3%) abolished the HPV(PA) in a reversible manner. The inhibition of HPV(PA) was completely reversed by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor. In contrast, the HPV(lung) was only partly decreased by CO. Moreover, the partial inhibition of HPV(lung) by CO was affected neither by the pretreatment with ODQ nor by NO synthase inhibitor (L-NAME). The CO-induced inhibitions of HPV(PA) and HPV(lung) were commonly unaffected by tetraethylammonium (TEA, 2 mM), a blocker of BK(Ca). As a whole, CO inhibits HPV(PA) via activating guanylate cyclase. The inconsistent effects of ODQ on HPV(PA) and HPV(lung) suggest that ODQ may lose its sGC inhibitory action when applied to the blood-containing perfusate.
Subject(s)
Animals , Rats , Hypoxia/physiopathology , Carbon Monoxide/pharmacology , Guanylate Cyclase/antagonists & inhibitors , NG-Nitroarginine Methyl Ester/chemistry , Nitric Oxide Synthase/antagonists & inhibitors , Oxadiazoles/chemistry , Pulmonary Artery/physiopathology , Quinoxalines/chemistry , Tetraethylammonium/chemistry , Vasoconstriction/drug effectsABSTRACT
A series of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives were synthesized and tested for in vitro leishmanicidal activity against amastigotes of Leishmania amazonensis in axenical cultures and murine infected macrophages. Structure-activity relationships demonstrated the importance of a radical methoxy at position R3', R4' and R5'. (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-1,4-dioxy-quinoxalin-2-yl)-propenone was the most active. Cytotoxicity on macrophages revealed that this product was almost six times more active than toxic.
Subject(s)
Animals , Female , Mice , Antiprotozoal Agents/chemistry , Cyclic N-Oxides/chemistry , Leishmania mexicana/drug effects , Quinoxalines/chemistry , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/toxicity , Cyclic N-Oxides/pharmacology , Cyclic N-Oxides/toxicity , Mice, Inbred BALB C , Macrophages/drug effects , Parasitic Sensitivity Tests , Quinoxalines/pharmacology , Quinoxalines/toxicity , Structure-Activity RelationshipABSTRACT
A number of pyrrolo [1.2-a]quinoxalines [3a-f], pyrimidol [1,6-a]quino-xalines [5a-c. 10.13]. pyrido[1.2-a]quinoxalines [6, 7a.b, 8a.b. 14]. [1.3] thiazino-[3,4-]quinoxalines [9, 11] and [1.3] oxazino [3,4-a]quinoxalines [12a.b] were obtained via interaction of 2-[3-methyl-1.2-dihydrquinoxalin-2-ylidene]malono-nitrile 2 with different reagents
Subject(s)
Nitriles/chemistry , Quinoxalines/chemistry , Anti-Bacterial AgentsABSTRACT
A series of coumarin derivatives bearing heterocyclic substituents was synthesized. Bromination of the key compound 8-acetyl-7-hydroxy-4-methylcoumarin [I] under varied conditions gave the brominated derivatives II, III and IV, Conversions of III by several cyclocondensations gave the corresponding thiazole V, quinoxaline VI, quinoxalinone VIII and furanone IX derivatives. Also, methylation and cyclocondensation of the methylene-active acetyl groups of II with several aldehydes gave the corresponding pyridone various amines gave the corresponding amino side chains. Some of these newly synthesized products were studied for their chemoprophylatic effect on Schistosoma mansoni infected mice. Compound Xc a showed moderate effect
Subject(s)
Animals, Laboratory , Heterocyclic Compounds/chemistry , Chemoprevention , Thiazoles/chemistry , Quinoxalines/chemistry , Schistosoma mansoni , MiceABSTRACT
2,3-dichloroquinoxaline I was allowed to react with hydrazine hydrate to give II. Reaction of II with some reagents afforded the products III-XI. Product X was utilized for synthesis of compounds XII-XXI via its reactions with active methylenes, nitriles and unsaturated systems
Subject(s)
Aza Compounds/chemical synthesis , Quinoxalines/chemistryABSTRACT
A convenient route is described for the preparation of s-triazolo [4, 3 - a] quinoxalines through the condensation reaction of 2 -chloro-3- hydrazino quinoxaline [I] with different aromatic aldehydes to afford the corresponding hydrazones [II]. 4- Chloro-1- aryl-1, 2, 4 -triazolo [4, 3 - a] quinoxalines [III] were prepared by the cyclization of [II] with bromine / acetic acid. The very reactive 4 chloro substituent was displaced by a variety of nucleophiles to yield 4 alkoxy [IV], or 4 - substituted amino - [V], or 4-diethyl malonyl ester [VI] of the 1 -aryl - 1, 2, 4 - triazolo [4, 3 - a] quinoxalines. Reaction of [VI] with phenyl hydrazine afforded 1 aryl 4 [1 - phenyl - 3,/ 5 - dioxo-pyrazolidin- 4-yl] 1,2,4-triazolo. [4, 3 - a] quinoxaline [VII]. The isolated ring system in which quinoxaline is incorporated with pyrazolinone [VIII] was achieved via the reaction of [I] with ethyl 2-methyl acetoacetate, then it was allowed to react with sodium methoxide to yield the 2 - methoxy - 3 -[3, 4 - dimethyl - 5 -oxo-pyrazolin - 1 - yl] quinoxaline [IX]. In addition, 2,3 - dichloroquinoxaline [C] was allowed to react with o - aminoacetophenone to give 2 - chloro - 3 - [0 - acetylanilino]-quinoxaline [X]