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Флехтер, О. Б.; Nigmatullina, L. R.; Karachurina, L. T.; Балтина, Л. А.; Zarudii, F. S.; Davydova, V. A.; Галин, Ф. З.; Толстиков, Г. А.

doi:10.1023/a:1010340121074

Cited by 11 publications

(10 citation statements)

References 4 publications

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“…[35][36][37][38] First, Jones oxidation was performed to convert betulin 1 into betulonic acid 2 (Scheme 1). 39 Betulin 1, a natural compound isolated from the bark of Betula species, is commercially available. [40][41][42] Next, the triazolization method was applied to betulonic acid 2 as the ketone source, using primary amines 3 and 4nitrophenyl azide 4, and the previously reported reaction conditions.…”

Section: Compound Synthesis and Structure-activity Relationshipmentioning

confidence: 99%

Betulonic acid derivatives inhibiting coronavirus replication in cell culture via the nsp15 endoribonuclease

Krasniqi

Stevaert

Loy

et al. 2020

Preprint

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The lack of medication to suppress coronavirus infections is a main reason for the dramatic course of the COVID-19 pandemic. There is an urgent need to identify suitable coronavirus drug targets and corresponding lead molecules. Here we describe the discovery of a class of coronavirus inhibitors acting on nsp15, a hexameric protein component of the viral replication-transcription complexes, endowed with immune evasion-associated endoribonuclease activity. SAR exploration of these 1,2,3-triazolo fused betulonic acid derivatives yielded lead molecule 5h as a strong inhibitor (antiviral EC50: 0.6 μM) of human coronavirus 229E replication. An nsp15 endoribonuclease active site mutant virus was markedly less sensitive to 5h, and selected resistance to the compound mapped to mutations in the N-terminal part of nsp15, at an interface between two nsp15 monomers. The biological findings were substantiated by the nsp15 binding mode for 5h, predicted by docking. Hence, besides delivering a distinct class of inhibitors, our study revealed a druggable pocket in the nsp15 hexamer with relevance for anti-coronavirus drug development.

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Section: Compound Synthesis and Structure-activity Relationshipmentioning

confidence: 99%

Betulonic acid derivatives inhibiting coronavirus replication in cell culture via the nsp15 endoribonuclease

Krasniqi

Stevaert

Loy

et al. 2020

Preprint

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“…In particular, C-2 condensation reactions of triterpene 2-hydroxymethylene derivatives to form open and cyclic heteroatomic compounds that exhibit various biological activities were described [6][7][8]. We prepared previously N-containing triterpenoids with pronounced immunotropic activity [9][10][11] that were promising for modification by a stable C-2 enaminone [12,13] via the reaction of lupane-and oleanane-type 2-hydroxymethylen-3-ones (1 and 5) with monoamines.…”

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Synthesis of C2 symmetric triterpene bis-enaminones

et al. 2012

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Mono-and dicondensed triterpene enaminones were prepared by reaction of oleanane-and lupane-type 2-hydroxymethylene derivatives with aliphatic and aromatic diamines in the presence of catalytic amounts of HOAc.The synthesis and biological properties of heteroatomic derivatives of betulin and betulinic acid have been the subject of many recent publications [1][2][3][4][5]. In particular, C-2 condensation reactions of triterpene 2-hydroxymethylene derivatives to form open and cyclic heteroatomic compounds that exhibit various biological activities were described [6][7][8]. We prepared previously N-containing triterpenoids with pronounced immunotropic activity [9-11] that were promising for modification by a stable C-2 enaminone [12, 13] via the reaction of lupane-and oleanane-type 2-hydroxymethylen-3-ones (1 and 5) with monoamines. An attempt to prepare symmetric condensation products of the triterpene 2-hydroxymethylene derivatives (1 and 5) with diamines under the published conditions [9] did not give the expected result. The resulting multi-component reaction mixture contained only traces of the mono-and dimeric products. That said, C 2 symmetric natural compounds and adducts with two triterpene moieties are interesting for medicinal chemistry [14][15][16][17][18].The goal of the present work was to study the possibility of targeted synthesis of C 2 symmetric bis-enaminones based on 2-hydroxymethylen-19E,28-epoxy-18D-olean-3-one (1) and 2-hydroxymethylen-3-oxolup-20(29)-en-28-oic acid methyl ester (5).The possibility of using the template method for targeted synthesis of the N-containing triterpene dimers was examined. Chelate complexes of phenylenediamines with Ni(NO 3 ) 2 ·6H 2 O [19] were tested for condensation with 1. The desired product formed only if the chelate complex of o-phenylenediamine was used. According to spectral data, the obtained product was quinoxalino[2,3-b]-19E,28-epoxy-18D-oleanane (2), which was synthesized previously by reaction of o-phenylenediamine with allobetulone (3) [20] or allobetulone diosphenol (4) [21].It was shown that condensation of o-phenylenediamine and oleanane diosphenol occurred most efficiently under acid-catalysis conditions [21]. In our instance, condensation of enolketones 1 and 5 with o-phenylenediamine formed monocondensed enaminones 6a and 7a in EtOH-PhH in the presence of catalytic amounts of AcOH regardless of the ratio of reagents (1:1 or 2:1).

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“…Compounds 20-23, 25, 26, and 28-31 (Scheme 3) with a pyridinylmethylidene substituent in the C-2 position were prepared via reaction of 3-oxotriterpenoids 1-3, 24, and 27 with 3-or 4-pyridinecarboxaldehydes in basic EtOH in analogy with the previous work [17] in 88-95% yields (after recrystallization). PMR spectra of 20-23, 25, 26, and 28-31 had the resonance for the methylidene proton at G 6.85-8.50 ppm.…”

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confidence: 99%

“…61.0, 121.1 (C-3c), 121.1 (C-5c), 128.1 (C-12), 138.6 (C-4c), 150.4 (C-2c), 150.4 (C-6c), 163.7 (C-7c), 170.2 (C-13), 175.4 (C 30 ONH), 199.8 (C-11), 217.1 (C-3).Synthesis of[14][15][16][17][18][19]. A solution of the acid hydrazides 10-13 (1 mmol) in EtOH (30 mL) was treated with 3-or 4-pyridinecarboxaldehyde (1.3 mmol), refluxed until the reaction was complete (TLC monitoring), and poured into HCl solution (100 mL, 5%).…”

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confidence: 99%

Conjugates of several lupane, oleanane, and ursane triterpenoids with the antituberculosis drug isoniazid and pyridinecarboxaldehydes

et al. 2011

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Conjugates of betulinic, oleanolic, ursolic, and glycyrrhetic acids and several of their derivatives with the antituberculosis drug isoniazid and 3-and 4-pyridinecarboxaldehydes were synthesized.Betulinic, oleanolic, ursolic, and glycyrrhetic acids have been successfully modified in the last decades to produce new biologically active compounds [1-6] of various structures including hydrazides and hydrazones [4] with antiviral and antitumor activity. It was shown recently that functionalization of the diterpenoid oxo-acid isosteviol by N-containing groups increased its antituberculosis activity, reducing the minimal inhibitory concentrations (MIC) from 50 to 1.5 Pg/mL [7]. Because antituberculosis activity is also typical of triterpenoids, namely betulin [8] and betulinic [8][9][10][11], oleanolic [10-13], and ursolic [10,14] acids, it seemed interesting to perform an analogous investigation of the isoprenoid series by studying the effect of their functionalization by the same N-containing groups that were used for isosteviol [7].Herein we report the synthesis of conjugates of betulinic, oleanolic, ursolic, and glycyrrhetic acids and 28-oxoallobetulone with the antituberculosis drug isoniazid (4-pyridinecarboxylic acid hydrazide) and 3-and 4-pyridinecarboxaldehydes.Mixed hydrazides 7-9 (Scheme 1) were synthesized via reaction of acid chlorides 4-6, which were prepared from triterpene acids 1-3, with isoniazid by refluxing in CHCl 3 in analogy with the previous work [15]. The target products were isolated by column chromatography in 71-77% yields. The PMR spectra turned out to be sufficiently characteristic to establish their structures. They showed resonances for amide protons at weak field (G 6.35 ppm, 8.15, 9.00-9.25, 10.15-10.90). Doubled resonances for the amide protons were noted in 7. This indicated that conformational equilibrium around the C(O)-N bond was occurring in solution. Protons of the pyridine rings of 7-9 appeared as doublets at G 7.56-7.68 (H-3c, H-5c) and 8.50-8.67 (H-2c, H-6c) ppm. 13 C NMR spectra exhibited resonances for C-28 (C-30) and C-7c at G 174.3-176.3 and 161.4-163.7 ppm.

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Cited by 11 publications

References 4 publications

Betulonic acid derivatives inhibiting coronavirus replication in cell culture via the nsp15 endoribonuclease

Betulonic acid derivatives inhibiting coronavirus replication in cell culture via the nsp15 endoribonuclease

Synthesis of C2 symmetric triterpene bis-enaminones

Conjugates of several lupane, oleanane, and ursane triterpenoids with the antituberculosis drug isoniazid and pyridinecarboxaldehydes

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