Magdy A. Zahran

Synthesis of Triazenopyrazole Derivativesas Potential Inhibitors of HIV-1

Summary. Ethoxymethylenemalononitrile and bis(methylthio)methylenemalononitrile were condensed with hydrazine hydrate to yield 5-aminopyrazole-4-carbonitrile (3a) and 5-amino-3-methylthiopyrazole-4-carbonitrile (3b), respectively. These compounds were treated with nitrous acid and coupled with different secondary amines to yield the triazenopyrazoles 4a–j. 5-(3,3-Diethyl-1-triazeno)pyrazole-4-carbonitrile (4c) was transferred into its two regioisomeric 2-deoxyribose nucleosides 5a,b which were subsequently hydrolyzed with H2O2/OH− to give the corresponding carboxamides 6a,b. All synthesized compounds were tested for biological activity against HIV-1 and herpes simplex virus, but only 4c showed moderate activity against HIV-1 with ED50=32μM.Zusammenfassung. Ethoxymethylenmalonitril und Bis(methlthio)methylenmalonitril wurden mit Hydrazinhydrat zu 5-Aminopyrazol-4-carbonitril (3a) und 5-Amino-3-methyltiopyrazol-4-carbonitril (3b) umgesetzt. Behandlung mit salpetriger Säure und Kupplung mit verschiedenen sekundären Aminen ergab die Triazenopyrazole 4a–j. 5-(3,3-Diethyl-1-triazeno)pyrazol-4-carbonitril (4c) wurde in seine beiden regioisomeren 2-Deoxyribonucleoside 5a,bübergeführt, welche anschließend mit H2O2/OH− zu den entsprechenden Carboxamiden 6a,b hydrolysiert wurden. Alle hergestellten Verbindungen wurden auf ihre biologische Aktivität gegenüber HIV-1 und Herpes simplex getestet. Nur 4c zeigte geringfügige Aktivität gegenüber HIV-1 (ED50=32μM).

Synthesis and reactions of 2-deoxy-β-D-ribofuranosyl derivatives of 3-aryl-4H-pyrrolo[2,3-d]pyrimidin-4-imines

Summary3-Aryl-7-(2-deoxy-β-D-erythro-pentofuranosyl)-3,7-dihydro-4H-pyrrolo[2,3-d]-pyrimidin-4-imines (4) as well as 4-arylamino-7-(2-deoxy-β-D-erythro-pentofuranosyl)-2-methyl-5-phenyl-7H-pyrrolo[2,3-d]pyrimidines (7) have been synthesized by glycosylation of the sodium salt of the corresponding nucleobases with 2-deoxy-3,5-di-O-p-toluyl-β-D-erythro-pentofuranosyl chloride (2) followed by subsequent deprotection with sodium methoxide in methanol. The deprotected nucleoside4 undergoes aDimroth rearrangement on reflux for 24 h in water to furnish the 4-arylamino nucleoside7.Zusammenfassung3-Aryl-7-(2-deoxy-β-D-erythro-pentafuranosyl)-3,7-dihydro-4H-pyrrolo[2,3-d]-pyrimidin-4-imine (4) und 4-Arylamino-7-(2-deoxy-β-D-erythro-pentofuranosyl)-2-methyl-5-phenyl-7H-pyrrolo[2,3,-d]pyrimidine (7) wurden durch Glycosylierung der Natriumsalze der entsprechenden Nucleosidbasen mit 2-Deoxy-3,5-di-O-p-toluyl-β-D-erythro-pentofuranosylchlorid (2) und anschließende Entfernung der Schutzgruppe mit Natriummethoxid in Methanol hergestellt. Das entschützte Nucleosid4 ergibt bei 24-stündigem Erhitzen in Wasser unter Rückfluß über eineDimroth-Umlagerung das 4-Aminonucleosid7.

Synthesis of 1-substituted indole-3-carboxaldehyde related to acyclic nucleosides and their condensed pyrenyl derivatives

Indole-3-carboxaldehyde was N-alkylated to give the corresponding acyclic nucleosides 3a–h which were condensed with 1-pyrenamine and 1-acetylpyrene to give 5a,c,e–g and 7b–d,e,g, respectively. The Schiffs bases 5a and 5e with 2-hydroxyethyl and methylthiomethyl N-1 substituents were found moderately active against HIV-1.

Synthesis of 3′-deoxy-3′-fluoro and -3′-amino nucleosides from 2-methylthiopyrimidin-4(1H)-ones

SummaryMethyl 2,3-dideoxy-3-fluoro-5-O-(4-phenylbenzoyl)-β-D-erythro-pentofuranoside (3) as well as 1,5-di-O-acetyl-2,3-dideoxy-3-phthalimodo-β-D-erythro-pentofuranose (12) were condensed with silylated 2-methylthiopyridin-4(1H)-ones2a, b in the presence of trimethylsilyl triflate as a catalyst to produce the corresponding nucleosides5, 6, 13. In these reactions, an endocyclic cleavage of C-O in3 took place; therefore, acyclic nucleosides4a, b were also formed. All 3′-fluoro nucleosides were deprotected with NH3/MeOH; the 3′-phthalimido nucleosides were deprotected with methylamine in ethanol. The latter method resulted in a concomitant substitution reaction in the pyrimidine moiety with replacement of the methylthio group. The 2-methylthio analogue of 3′-deoxy-3′-fluorothylmidine showed moderate activity against HIV-1.ZusammenfassungMethyl-2,3-didesoxy-3-fluoro-5-O-(4-phenylbenzoyl)-β-D-erythro-pentofuranosid (3) und 1,5-di-O-Acetyl-2,3-didesoxy-3-phthalimido-β-D-erythro-pentofuranose (12) wurden in Gegenwart von Trimethylsilyltriflat als Katalysator mit den silylierten 2-Methylthiopyridin-4(1H)-onen2a, b zu den entsprechenden Nucleosiden5–6 und13 kondensiert. Bei diesen Reaktionen tritt als Nebenreaktion eine Öffnung der endocyclischen C-O — Bindung auf, sodaß auch die acyclischen Nucleoside4a, b gebildet werden. Die 3′-Fluoronucleoside wurden mit NH3/MeOH entschützt, die 3′-Phthalimidonucleoside mit Methylamin in Ethanol. Letztere Reaktion resultierte in eine gleichzeitigen Substitution der Pyrimidineinheit unter Austausch der Methylthiogruppe. Das 2-Methylthioanalogon zu 3′-Desoxy-3′-fluorthymidin zeigt mäßige Aktivität gegen HIV-1.