[Nitrobenzofuroxane derivatives as dual action hiv-1 inhibitors]. / Proizvodnye nitrobenzofuroksanov v kachestve ingibitorov VICh-1 dvoinogo deistviia.

Human immunodeficiency virus first type (HIV-1) is a main cause of one of the most dangerous diseases, AIDS. The search for new inhibitors of the virus still remains an urgent task. One approach to suppress the HIV infection is to use a double-acting inhibitors, i.e. inhibitors directed to two stages of the viral life cycle. The catalytic domain of HIV-1 integrase has a similar spatial organization with ribonuclease (RNase H) domain of HIV-1 reverse transcriptase, and approach aimed to create HIV-1 integrase and RNase H double-acting is very promising. In this work we synthesized a series of 6-nitrobenzofuroxane derivatives and studied their ability to inhibit two viral enzymes - integrase and RNase H HIV-1.

Structural-Functional Analysis of 2,1,3-Benzoxadiazoles and Their N-oxides As HIV-1 Integrase Inhibitors.

Human immunodeficiency virus type 1 integrase is one of the most attractive targets for the development of anti-HIV-1 inhibitors. The capacity of a series of 2,1,3-benzoxadiazoles (benzofurazans) and their N-oxides (benzofuroxans) selected using the PASS software to inhibit the catalytic activity of HIV-1 integrase was studied in the present work. Only the nitro-derivatives of these compounds were found to display inhibitory activity. The study of the mechanism of inhibition by nitro-benzofurazans/benzofuroxans showed that they impede the substrate DNA binding at the integrase active site. These inhibitors were also active against integrase mutants resistant to raltegravir, which is the first HIV-1 integrase inhibitor approved for clinical use. The comparison of computer-aided estimations of the pharmacodynamic and pharmacokinetic properties of the compounds studied and raltegravir led us to conclude that these compounds show promise and need to be further studied as potential HIV-1 integrase inhibitors.

[Peripheral mechanisms of action of oxatriazolium-5-olate derivative 3-(3-[1,2,4]-triazolo)oxatriazolium-5-olate in spontaneously hypertensive rats].

It is shown that 3-(3-[1,2,4]-triazolo)-oxatriazolium-5-olate (azasidnon-6) can act directly on the vascular wall of isolated segments of caudal ventral artery of SHR rats. Using heme-dependent soluble guanyl cyclase inhibitor 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), it has been found that one of the possible mechanisms of azasidnon-6 vasodilatory action includes heme-dependent activation of a soluble form of guanylate cyclase.

[Hypotensive effect of oxatriazolo-5-olate derivative in chronic experiments on SHR rats].

Long-term peroral administration of the oxatriazolo-5-olate derivative azasydnon-6 leads to a decrease in the systolic arterial blood pressure in SHR rats. The hypotensive effect of azasydnon-6 is mediated by stimulation of the sGC-cGMP pathway, which triggers vasodilatation of SMC in vessels. The drug effect is inhibited by 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one, a selective sGC inhibitor. During long-term treatment, no tolerance to azasydnon-6 is developed in isolated arterial vessels.

[Hypotensive effect of oxatriazolium-5-olate derivative].

Intravenous administration of azasidnon-6 (oxatriazolium-5-olate derivative) induces prolonged dose-dependent decrease in arterial blood pressure in awake Wistar and SHR rats. Hypotensive effects of azasidnon-6 in SHR rats is significantly higher during inhibition of endogenous NO synthesis.

Effects of N-nitropyrazoles on ocular blood flow of rabbits and retinal function recovery of rat eyes after ischemic insults.

Twelve compounds of N-nitropyrazoles were studied for their effects on ocular blood flow in rabbits and retinal function recovery in rat eyes after ischemic insults. Of the twelve N-nitropyrazoles examined, nine increased choroidal blood flow while five increased retinal blood flow significantly. On the other hand, all twelve compounds increased blood flow in iris and ciliary muscle without exception. As for retinal function recovery after ischemic insult in rat eyes, eight out of the twelve compounds showed more significant facilitation than the control. The structure activity relationship of the N-nitropyrazoles to increase ocular blood flow and to facilitate retinal function recovery after ischemic insults were discussed.