Synthesis and biological evaluation of some new mono Mannich bases with piperazines as possible anticancer agents and carbonic anhydrase inhibitors

New mono Mannich bases, (2-(4-hydroxy-3-((4-substituephenylpiperazin-1-yl)methyl)benzylidene)-2,3-dihydro-1H-inden-1-one), were prepared to evaluate their cytotoxic/anticancer properties and also their inhibitory effects on human carbonic anhydrase I and II isoenzymes (hCA I and II). Amine part was changed as [N-phenylpiperazine (1), N-benzylpiperazine (2), 1-(2-fluorophenyl)piperazine (3), 1-(4-fluorophenyl)piperazine (4), 1-(2-methoxyphenyl)piperazine (5)]. The structure of the synthesized compounds was characterized by ¹H NMR, ¹³C NMR and HRMS spectra. Cytotoxicity results of the series pointed out that the compound 4 had the highest tumor selectivity value (TS: 59.4) possibly by inducing necrotic cell death in series. Additionally, all compounds synthesized showed a good inhibition profile towards hCA I and II isoenzymes with the Ki values between 29.6 and 58.4 nM and 38.1–69.7 nM, respectively. These values were lower than the reference compound AZA. However, it seems that the compounds 4 and 2 can be considered as lead compounds of CA studies with the lowest Ki values in series for further designs.     

Phytochemical investigation of Millettia dorwardi Coll. et Hemsl

The first phytochemical investigation on the vine stems of Millettia dorwardi Coll. et Hemsl led to the isolation of ten flavonoids (isoafrormosin 1, formononetin 2, afrormosin 3, padmakastein 4, liquiritigenin 5, 4H-1-Benzopyran-4-one,7-hydroxy-5,8-dimethoxy-3-(4-methoxyphenyl)-isoflavone 6, 4H-1-Benzopyran-4-one,7-hydroxy-3-(3-hydroxy-5-methoxyphenyl)-6-methoxy 8, 4H-1-Benzopyran-4-one,6-methoxy-3-(4-methoxyphenyl)-6,4′-dimethoxyisoflavone 9, irisolidone 10, prunetin 11), one heterocycle (5-5′-dibuthoxy-2-2′-bifuran 7) and one new isoflavone glycoside (4H-1-Benzopyran-4-one,5-hydroxymethyl-3-(4-methoxyphenyl)-6-β-d-glucopyranoside-isoflavone 12). Their structures were determined by extensive analysis of their spectroscopic data. Among them, compounds 4, 6–10, 12 were for the first time isolated from this genus. The chemotaxonomic importance of these compounds was also summarized.     

Chemical constituents from the fresh flower buds of Musa nana and their chemotaxonomic significance

Phytochemical study on the fresh flower of Musa nana Lour. provided seventeen known compounds including two alkaloids, 3-(hydroxyacetyl)-indole (1), bi-indol-3-yl (2), two terpenoids, 5-[(1R)-1-hydroxy-2,6,6-trimethyl-4-oxo-2-cyclohexen-1-yl]-3-methyl-, (2Z, 4E) −2, 4-pentadienoic acid (Valdes), 5, 6(S), 7, 7a(R)-tetrahydro-6-hydroxy-4,4-dimethyl-2(4H)-benzofuranone (4), seven phenols (5–11), three phenylphenalenones, 2-hydroxy-4-(4-methoxyphenyl)-1H-phenalen-1-one (12), 2-methoxy-9-phenyl-1H-phenalen-1-one (13), 2-methoxy-9-(4-methoxyphenyl)-1H-phenalen-1-one (14), and three lipids (15–17). In the present study, all the compounds were isolated for the first time from the species M. nana. Ten compounds including 1-8 and 15-16 have never been previously encountered in the Musaceae family. Furthermore, the chemotaxonomic significance of these isolates was also discussed.     

New azafluorenones with cytotoxic and carbonic anhydrase inhibitory properties: 2-Aryl-4-(4-hydroxyphenyl)-5H-indeno[1,2-b]pyridin-5-ones

New azafluorenones, 2-aryl-4-(4-hydroxyphenyl)-5H-indeno[1,2-b]pyridin-5-ones, were prepared to evaluate their cytotoxic/anticancer properties, also their inhibitory effects on hCA I and II isoenzymes. Aryl part was changed as [phenyl (H1), 4-methylphenyl (H2), 4-methoxyphenyl (H3), 4-fluorophenyl (H4), 4-bromophenyl (H5), 4-chlorophenyl (H6), 3-hydroxyphenyl (H7), and 4-hydroxyphenyl (H8)]. The structure of the synthesized compounds was characterized by ¹H NMR, ¹³C NMR and HRMS spectra.Cytotoxicity results of the series pointed out that the compounds H6 (PSE: 28.0) and H5 (PSE: 27.3), with the highest potency selectivity expression (PSE) value, can be considered as leader compounds of the study in designing novel anticancer agents. Additionally, all azafluorenones synthesized showed a good inhibition profile towards hCA I and II isoenzymes in the range of 54.14–73.72 nM and 67.28–76.15 nM, respectively.The compounds H5 and H6 can be considered for further designs with their cytotoxic and CA inhibitory profiles.     

The inhibitory effects of phenolic Mannich bases on carbonic anhydrase I and II isoenzymes

Phenolic mono Mannich bases [2-[4-hydroxy-3-(aminomethyl)benzylidene]-2,3-dihydro-1H-inden-1-one (8–15)] and bis Mannich bases [2-[4-hydroxy-3,5-bis(aminomethyl)benzylidene]-2, 3-dihydro-1H-inden-1-one (2–7)] were synthesized starting from 2-(4-hydroxybenzylidene)-2, 3-dihydro-inden-1-one (1). This study was designed in order to investigate the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory properties of a library of compounds incorporating the phenol functional group. All prepared compounds showed a low inhibition percentages on both human (h) isoforms hCA I and hCA II compared to the reference sulfonamide acetazolamide. Mannich bases 2–15 had lower inhibition percentages than the compound 1 on hCA I and hCA II, except compound 14, which is a Mannich base derivative of dipropylamine, which had a similar inhibitory power as compound 1 on hCA II. All compounds synthesized 1–15 were 1.3–1.9 times more effective on hCA II comparing with the effectivenes of the compounds on hCA I.     

A new homoisoflavonoid and the bioactivities of some selected homoisoflavonoids from the inter-bulb surfaces of Scilla nervosa subsp. rigidifolia

Seven homoisoflavonoids and one stilbenoid, 3-(4′-methoxybenzyl)-6,7-dihydroxy-5-methoxychroman-4-one (1) which is new; 3-(4′-methoxybenzyl)-6-hydroxy-5,7-dimethoxychroman-4-one (2); 3-(4′-methoxybenzyl)-5,7-dimethoxychroman-4-one (3); 3-(3′-hydroxy-4′-methoxybenzyl)-5,7-dimethoxychroman-4-one (4); 3-(4′-methoxybenzylidene)-5,7-dihydroxy-6-methoxychroman-4-one (5); 3-(4′-hydroxybenzylidene)-5,7-dihydroxy-6-methoxychroman-4-one (6); 3-(4′-hydroxybenzylidene)-5,7-dihydroxychroman-4-one (7) and 4,3′,5′-trihydroxy-3-methoxystilbene (8), were isolated from the yellow inter-bulb deposits from Scilla nervosa. The structures of these compounds were elucidated by 1D- and 2D-NMR and mass spectrometry. A number of extracts, fractions and compounds tested displayed bacterostatic activity with MICs ranging between 0.156 and 1.250 mg/ml. Two extracts displayed significant α-glucosidase inhibitory activity and a number of extracts, fractions and compounds showed strong antioxidant activity with, compounds 1, 2 and 8 displaying lower MECs than the positive control ascorbic acid (0.0156 mg/ml).     

Homoisoflavonoids from the inter-bulb surfaces of Scilla nervosa subsp. rigidifolia

Eight homoisoflavonoids, two of which are new: 3-(4′-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (1); 3-(4′-methoxybenzyl)-5,7-dimethoxychroman-4-one (2); 3-(4′-methoxybenzyl)-7-hydroxy-5,6-dimethoxychroman-4-one (3); 3-(4′-methoxybenzyl)-6-hydroxy-5,7-dimethoxychroman-4-one (4); 3-(3′-hydroxy-4′-methoxybenzyl)-5,7-dihydroxy-6-methoxychroman-4-one (5); 3-(3′-hydroxy-4′-methoxybenzyl)-5,7-dihydroxychroman-4-one (6); 3-(4′-hydroxybenzylidene)-5,7-dihydroxy-6-methoxychroman-4-one (7) and 3-(4′-hydroxybenzylidene)-5,7-dihydroxychroman-4-one (8), were isolated from the yellow Inter-bulb deposits from Scilla nervosa. The structures of these compounds were elucidated and characterized by 1D- and 2D-NMR and mass spectrometry. The structures of the known compounds were compared to those ones in literature.     

Chemical constituents from the roots of Acanthus ilicifolius var. xiamenensis

Chemical investigation of Acanthus ilicifolius var. xiamenensis led to the isolation of eleven compounds, and their structures were identified to be 2-benzoxazolinone (1), 2-hydroxy-2H-1,4-benzoxazin-3(4H)-one (2), (2R)-2-O-β-d-glucopyranosyl-2H-1,4-benzox azin-3(4H)-one (3), (2R)-2-O-β-d-glucopyranosyl-4-hydroxy-2H-1,4-benzoxazin-3(4H)-one (4), (2R)-2-O-β-d-glucopyranosyl-7-hydroxy-2H-1,4-benzoxazin-3(4H)-one (5), lyoniside (6), 3′-methoxy-luteolin-7-O-β-d-glucopyranoside (7), β-sitosterol-3-O-β-d-glucopyranoside (8), stigmasterol octadecanoate (9), β-sitosterol octadecanoate (10), stigmasterol-3-O-β-d-glucopyranoside (11) on the basis of mass and NMR spectra. This is the first report on the occurrence of compound 6 and 7 in Acanthaceae. This work also represents the first phytochemical work on the roots of A. ilicifolius var. xiamenensis.     

Three new 3-methyl-2-arylbenzofurans from the fermentation products of an endophytic fungus Phomopsis sp. and their anti-TMV activity

Three new arylbenzofurans, 7-methoxy-2-(4-methoxyphenyl)-3-methyl-5-(3-prenyl)-benzofuran (1), 2-(4-methoxyphenyl)-3-methyl-5-(3-prenyl)-benzofuran-7-ol (2), 2-(4-hydroxy-3,5-dimethoxyphenyl)-3-methyl-5-(3-prenyl)benzofuran-7-ol (3), along with four known arylbenzofurans (4–7) were isolated from the fermentation products of an endophytic Phomopsis sp. Their structures were elucidated by spectroscopic methods including extensive 1D- and 2D-NMR techniques. In addition, compounds 1–7 were tested for their anti-tobacco mosaic virus (anti-TMV) activity. The results showed that compound 3 exhibited obvious anti-TMV activity with inhibition rate of 35.2% better than that of positive control (31.8%). The other compounds also showed potential anti-TMV activity with inhibition rates in the range of 18.6–25.7%, respectively.     

Anti-tobacco mosaic virus phenylpropanoids from the stems of Nicotiana tabacum

Three new phenylpropanoids, 3-(6-methoxy-3-oxo-1, 3-dihydroisobenzofuran-5-yl)-3-oxopropyl acetate (1), 3-hydroxy-1-(6-methoxy-1, 3-dihydroisobenzofuran-5-yl)propan-1-one (2), and 3-hydroxy-1-(6- methyl-1, 3-dihydroisobenzofuran-5-yl)propan-1-one (3), together with three known phenylpropanoids (4–6) were isolated from the stems of Nicotiana tabacum. Their structures were examined using different spectroscopic techniques, including extensive 1D- and 2D NMR. Compounds 1–6 were also evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The anti-TMV results demonstrated that compounds 1 and 6 exhibited high anti-TMV activities, with inhibition rates of 34.6 and 35.4%, both of which were higher than the positive control (32.5%). The other compounds (2–5) also had anti-TMV activities, with inhibition rates between 16.8 and 28.6%.     

SYA 013 analogs as moderately selective sigma-2 (σ2) ligands: Structure-affinity relationship studies

Several lines of evidence suggest that selective sigma-2 (σ₂) ligands might be useful for the treatment of solid tumors. However, very few selective σ₂ ligands have been identified. This study was aimed at identifying new selective σ₂ receptor ligands using a previously identified agent, SYA 013 as a lead. Four groups, homopiperazine, piperazine, tropane and selected oxime analogs of the homopiperazines were identified, synthesized and subsequently screened at the σ₁ and σ₂ receptors. The results demonstrate that these scaffolds can be modified to obtain selective σ₂ receptor ligands. 1-(5-Chloropyridin-2-yl)-4-(3-((4-fluorophenyl)thio)propyl)-1,4-diazepane, 7 and 3-(4-chlorophenyl)-8-(3-((2-fluorophenyl)thio)propyl)-8-azabicyclo[3.2.1]octan-3-ol, 21 were identified as the highest binding affinity ligands (σ₂Ki = 2.2 nM) and (4-(4-(5-chloropyridin-2-yl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)-butan-1-one oxime, 22 as a high affinity and the most selective ligand for the σ₂ receptor (σ₁Ki/σ₂Ki = 41.8).     

Steroidal constituents of Solanum xanthocarpum

From the extract of the fruits of Solanum xanthocarpum (Solanaceae), five new steroidal compounds were isolated and characterized: 4α-methyl-24ξ-ethyl-5α-cholest-7-en-3β,22ξ-diol (1), 3β,22ξ-dihydroxy-4α-methyl-24ξ-ethyl-5α-cholest-7-en-6-one (2), 3β-benzoxy-14β,22ξ-dihydroxy-4α-methyl-24ξ-ethyl-5α-cholest-7-en-6-one (3), 3β-benzoxy-14α,22ξ-dihydroxy-4α-methyl-24ξ-ethyl-5α-cholest-7-en-6-one (4) and 3β-(p-hydroxy)-benzoxy-22ξ-hydroxy-4α-methyl-24ξ-ethyl-5α-cholest-7-en-6-one (5).     

Phenylethanoid glycosides from the leaves of Magnolia hodgsonii

Three new phenylethanoid glycosides, 2-(3-hydroxy-4-methoxyphenyl)ethyl 1-O-β-d-allopyranoside (hodgsonialloside A, 1), 2-(3-hydroxy-4-methoxyphenyl)ethyl 1-O-β-d-glucopyranosyl-(1 → 4)-β-d-allopyranoside (hodgsonialloside B, 2) and 2-(3-methoxy-4-hydroxyphenyl)ethyl 1-O-β-d-allopyranoside (hodgsonialloside C, 3) were isolated from the leaves of Magnolia hodgsonii in addition to six known compounds, tyrosol 4-O-β-d-xylopyranosyl-(1 → 6)-β-d-glucopyranoside (4), kaempferol 3-O-neohesperidoside (5), kaempferol 3-O-rutinoside (6), kaempferol 3-O-α-l-rhamnopyranosyl-(1 → 2)-[α-l-rhamnopyranosyl-(1 → 6)]-β-d-glucopyranoside (7), (+)-syringaresinol O-β-d-glucopyranoside (8), and oblongionoside C (9). The structure elucidation of these compounds was based on analyses of physical and spectroscopic data including 1D and 2D NMR experiments.     

Eudesmane-type sesquiterpenes from the liverwort Apomarsupella revolute

Phytochemical investigation of the Et₂O extract of liverwort Apomarsupella revolute led to isolation and identification of five new eudesmane-type sesquiterpenoids, 6β-hydroxy-9β-acetoxy-eudesma-4,11-dien (1), 6β-hydroxy-9β-acetoxy-eudesma-4,11-dien-3-one (2), 5α,6β-dihydroxy-9β-acetoxy-eudesma-4(15),11-dien (3) 4β-hydroxy-9β-acetoxy-11,12,13-trinor-5-eudesmen-7-one (4) and 4β-methox-9β-acetoxy-11,12,13-trinor-5-eudesmen-7-one (5), two of which were trinorsesquiterpenoids. Their structures were established unequivocally on the basis of spectroscopic data analysis. All compounds were preliminary bioscreened for their cytotoxicities and antifungal activities.     

Synthesis and preliminary evaluation of pharmacological properties of some piperazine derivatives of xanthone

A series of 9 piperazine derivatives of xanthone were synthesized and evaluated for cardiovascular activity. The following pharmacological experiments were conducted: the binding affinity for adrenoceptors, the influence on the normal electrocardiogram, the effect on the arterial blood pressure and prophylactic antiarrhythmic activity in adrenaline induced model of arrhythmia (rats, iv). Three compounds revealed nanomolar affinity for α₁-adrenoceptor which was correlated with the strongest cardiovascular (antiarrhythmic and hypotensive) activity in animals’ models. The most promising compound was 4-(3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (12) which revealed antiarrhythmic activity with ED₅₀ value of 0.69 mg/kg in adrenaline induced arrhythmia (rats, iv). Other synthesized xanthone derivatives, that is, (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (10) and (R,S)-4-(2-acetoxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (11) also acted as potential antiarrhythmics in adrenaline induced model of arrhythmia in rats after intravenous injection (ED₅₀ = 0.88 mg/kg and 0.89 mg/kg, respectively). These values were lower than values obtained for reference drugs such as propranolol and urapidil, but not carvedilol.Results were quite promising and suggested that in the group of xanthone derivatives new potential antiarrhythmics and hypotensives might be found.     

New derivatives from the aerial parts of Boerhaavia diffusa L. (Nyctaginaceae)

Boerhaavia diffusa L. is used in the traditional medicine of several Asian countries. The isolation and identification of five new compounds, together with 11 known compounds, from the ethyl acetate extract of the aerial part of B. diffusa grown Vietnam is reported. The structure of the new compounds was established by 1D and 2D NMR spectroscopy, and high resolution ESI-MS analysis. New compounds are two rotenoids: 9,11-dihydroxy-6,10-dimethoxy[1]benzopyrano[3,4-b][1]benzopyran-12(6H)-one (boeravinone P, 3) and 3-[2-(β-d-glucopyranosyloxy)-3-hydroxyphenyl]-5-hydroxy-2-hydroxymethyl-7-methoxy-6-methyl-4H-1-benzopyran-4-one (boeravinone Q, 9), an atropisomeric mixture of two rotenoid glycosides (3′,5-dihydroxy-2-hydroxymethyl-7-methoxy-6-methylisoflavone 2′-O-β-d-glucopyranoside, 11), a sesquiterpene lactone (4,10-dihydroxy-8-methoxyguai-7(11)-en-8,12-olide, 5) and a new phenylpropanoid glycoside (boerhaavic acid, 15).     

Synthesis and evaluation of pharmacological properties of some new xanthone derivatives with piperazine moiety

A series of new xanthone derivatives with piperazine moiety [1–7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α₁ and β₁ adrenergic as well as 5-HT_1A, 5-HT₆ and 5-HT_7b serotoninergic receptors. Five of the tested compounds were also evaluated for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic 5-HT_1A receptors (K_i = 24 nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED₅₀ determined in maximal electroshock (MES) seizure assay was 105 mg/kg b.w. (rats, p.o.). Combining of xanthone with piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral administration.     

Synthesis of thiazole-based substituted piperidinone oximes: Profiling of antioxidant and antimicrobial activity

The synthesis of novel thiazole-based piperidinone oximes and screening of their antioxidant and antimicrobial activity are described. The obtained results revealed that the electronic effects of active substituents at C-4 terminals of phenyl rings on either side of piperidinone skeleton, as well as at 2-hydrazinyl thiazole, played a major role in development of antioxidant and antimicrobial activity. Antioxidant activity seems to be based also on radical dissipating ability of the thiazole ring. The nucleophilic character of sulfur in thiazole and lipophilic nature of piperidinone skeleton substantially influenced the observed antimicrobial activity of thiazole-based piperidinone oximes. Among the synthesized compounds, 2,6-bis(4-hydroxy-3-methoxyphenyl)-1-methylpiperidin-4-one O-(2-(2-(4-hydroxy-3-methoxybenzylidene)hydrazinyl)thiazol-4-yl) oxime exhibited excellent antioxidant activity whereas compound 2,6-bis(4-chloro phenyl)-1-methylpiperidin-4-one O-(2-(2-(4-nitrobenzylidene)hydrazinyl)thiazol-4-yl)oxime emerged as an outstanding antimicrobial agent.     

Phytochemicals from the stem wood of Sorbus lanata (D. Don.) Schauer

Three new phenolic compounds, sorlanin (4-(3-(hydroxymethyl)-5-methoxy-7-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-2-methoxyphenol, 1), sorbanin (2-((3,5-dimethoxy-[1,1′-biphenyl]-4-yl)oxy)-1-(4-hydroxy-3-methoxyphenyl)propane-1,3-diol, 2) and sorbalanin (4-(3-(hydroxymethyl)-5,6-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxino[2,3-g]benzofuran-2-yl)-2-methoxyphenol, 3), together with eight known compounds, polystachyol (4), isolariciresinol (5), dihydrodehydrodiconiferyl alcohol (6), tuberculatin (7), ovafolinin E (8), aucuparin (9), 2′-methoxyaucuparin (10), and tetracosyl-3-(3,4-dihydroxyphenyl)acrylate (11), were isolated from Sorbus lanata. The structures of these phytoconstituents were elucidated through extensive spectroscopic techniques, including UV, IR, 1D and 2D NMR, ESI-MS and HRESI-MS experiments. All the compounds except 9 and 10 were isolated for the first time from the genus Sorbus. The isolated compounds were also tested in DPPH radical scavenging reaction where compounds 6, 7, 10 and 11 showed significant activities with IC₅₀ values of 9.2, 11.7, 23.0 and 33.7 μM, respectively.     

Two new coumarin derivatives from the whole plant of Spermacoce latifolia

Six coumarin derivatives including two new, 2-acetyl-4-hydroxy-6H-furo[2,3-g]chromen-6-one (1) and 2-(1',2'-dihydroxypropan-2'-yl)-4-hydroxy-6H-furo[2,3-g]chromen-6-one (2), and four known ones, 7H-furo [3,2-g][1]benzopyran-7-one (3), esculetin (4), isoscopoletin (5) and 7,8-dihydroxy-6-methoxycoumarin (6), were isolated for the first time from the whole plant of Spermacoce latifolia. Their structures were determined by detailed spectroscopic analysis and comparison with literature reported data. In vitro antibacterial assay indicated that compounds 1, 2 and 4 were active toward bacteria Staphyloccocus aureus, Bacillus subtilis and Bacillus cereus with MIC values ranging from 7.81 to 62.5 ug/mL.