Three further naphthoquinones produced by Fusarium solani

Three naphthoquinone pigments are described which were produced by Fusarium solani. They are 2,3-dihydro-5,8-dihydroxy-6-methoxy-2-hydroxymethyl-3-(2-hydroxypropyl)-1,4-naphthalenedione, 2,3-dihydro-5-hydroxy-4-hydroxymethyl-8-methoxy-naphtho[1,2-b]furan-6,9-dione and 5,8-dihydroxy-2-methoxy-6-hydroxymethyl-7-(2-hydroxypropyl)-1,4-naphthalenedione. One of these pigments was shown to be the precursor of the other two.     

Synthesis and evaluation of bioactive naphthoquinones from the Brazilian medicinal plant, Tabebuia avellanedae

A series of naphthoquinones based on the naphtho[2,3-b]furan-4,9-dione skeleton such as (−)-5-hydroxy-2-(1′-hydoxyethyl)naphtho[2,3-b]furan-4,9-dione (1) and its positional isomer, (−)-8-hydroxy-2-(1′-hydoxyethyl)naphtho[2,3-b]furan-4,9-dione (2), which are secondary metabolites found in the inner bark of Tabebuia avellanedae, were stereoselectively synthesized and their biological activities were evaluated in conjunction with those of their corresponding enantiomers. Compound 1 exhibited potent antiproliferative effect against several human tumor cell lines, but its effect against some human normal cell lines was much lower than that of mitomycin. On the other hand, its enantiomer (R)-1 was less active toward the above tumor cell lines than 1. The antiproliferative effect of 2 against all tumor cell lines was significantly reduced. These results indicated the presence of the phenolic hydroxy group at C-5 is of great important for increasing antiproliferative effect. In addition, 1 also showed higher cancer chemopreventive activity than 2, while there were no significant differences between 1 and 2 in antimicrobial activity. Both compounds displayed modest antifungal and antibacterial activity (Gram-positive bacteria), whereas they were inactive against Gram-negative bacteria.     

Difuranonaphthoquinones from Plumbago zeylanica roots

The naphthoquinones, lapachol (1), plumbagin (2), 2-isopropenyl-9-methoxy-1,8-di-oxa-dicyclopenta[b,g]naphthalene-4,10-dione (3), 9-hydroxy-2-isopropenyl-1,8-dioxa-dicyclopenta[b,g]naphthalene-4,10-dione (4), 2-(1-hydroxy-1-methyl-ethyl)-9-methoxy-1,8-dioxa-dicyclopenta[b,g]naphthalene-4,10-dione (5) and 5,7-dihydroxy-8-methoxy-2-methyl-1,4-naphthoquinone (6) were isolated isolated from roots of Plumbago zeylanica. The new constituents (3–5) in addition to known compounds (1, 2 and 6) were characterized by spectral analysis (UV, IR, 1D & 2D NMR and MS).     

Antiproliferative activity of synthetic naphthoquinones related to lapachol. First synthesis of 5-hydroxylapachol

A series of 5-hydroxy-1,4-naphthoquinones analogues was synthesized from juglone (6) and their antiproliferative activity against a representative panel of six human solid tumor cell lines has been investigated. The 2,5-dihydroxy-3-(3-methylbut-2-enyl)naphthalene-1,4-dione (4) and 2,3-dihydro-5-hydroxy-2-(prop-1-en-2-yl)naphtho[2,3-b]furan-4,9-dione (27) were the most potent antiproliferative agents with GI₅₀ values of 0.42–8.1 and 0.80–2.2 μM, respectively. The results provide insight into the correlation between some structural properties of 5-hydroxynaphthoquinones and their antiproliferative activity.     

Metabolites from Penicillium sp., an endophytic fungus from the liverwort Riccardia multifida (L.) S. Gray

Two new metabolites, (3aR,9bR)-6,9b-dihydroxy-8-methoxy-1-methylcyclopentene[c]isochromen-3,5-dione (1) and 6-hydroxyl-deoxyfunicone (2), together with five known compounds (3–7), were obtained from Penicillium sp., an endophytic fungus from the Chinese liverwort Riccardia multifida (L.) S. Gray. Their structures were determined by extensive analysis of their spectroscopic data. Allelopathic test showed that compounds 2 and 4 significantly retarded germination of Arabidopsis thaliana seeds.     

Antiplasmodial anthraquinones and hemisynthetic derivatives from the leaves of Tectona grandis (Verbenaceae)

Chemical investigation of the methanol extract of the leaves of Tectona grandis led to the isolation of one new anthraquinone derivative, grandiquinone A (3-acetoxy-8-hydroxy-2-methylanthraquinone) (1), along with nine known compounds: 5,8-dihydroxy-2-methylanthraquinone (2), hydroxysesamone (3), 3-hydroxy-2-methylanthraquinone (4), quinizarine (5), betulinic acid (6), ursolic acid (7), tectograndone (8), corosolic acid (9) and sitosterol 3-O-β-d-glucopyranoside (10). Compounds 2 and 3 were isolated for the first time from the leaves of this plant, while 5 has never been reported from the genus Tectona. Hydroxysesamone (3) and tectograndone (8) were subjected to cyclisation and acetylation reactions to afford two hemisynthetic derivatives, 6,9-dihydroxy-2,2-(dimethyldihydropyrano)-3,4-dihydro-2H-benzo[g]chromene-5,10-dione (11) and acetyltectograndone (12) respectively, which are reported here for the first time. The ethyl acetate-soluble portion, some of the isolated compounds and hemisynthetic derivatives were evaluated for their antiplasmodial activity against the multidrug-resistant Dd2 strain of Plasmodium falciparum. Compound 3 showed a prominent activity, while 2, 8, 9, 11 and 12 showed significant in vitro anti-malarial activity. Compound 1 was weakly active in this test. The structures of the compounds were elucidated by spectroscopic methods and comparison of the data with the literature.     

α-Glucosidase Inhibition by Usnic Acid Derivatives

This study investigated a set of new potential antidiabetes agents. Derivatives of usnic acid were designed and synthesized. These analogs and nineteen benzylidene analogs from a previous study were evaluated for enzyme inhibition of α-glucosidase. Analogs synthesized using the Dakin oxidative method displayed stronger activity than the pristine usnic acid (IC₅₀>200 μM). Methyl (2E,3R)-7-acetyl-4,6-dihydroxy-2-(2-methoxy-2-oxoethylidene)-3,5-dimethyl-2,3-dihydro-1-benzofuran-3-carboxylate ( 6b ) and 1,1′-(2,4,6-trihydroxy-5-methyl-1,3-phenylene)di(ethan-1-one) ( 6e ) were more potent than an acarbose positive control (IC₅₀ 93.6±0.49 μM), with IC₅₀ values of 42.6±1.30 and 90.8±0.32 μM, respectively. Most of the compounds synthesized from the benzylidene series displayed promising activity. (9bR)-2,6-Bis[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one ( 1c ), (9bR)-3,7,9-trihydroxy-8,9b-dimethyl-2,6-bis[(2E)-3-phenylprop-2-enoyl]dibenzo[b,d]furan-1(9bH)-one ( 1g ), (9bR)-2-acetyl-6-[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one ( 2d ), (9bR)-2-acetyl-6-[(2E)-3-(3-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one ( 2e ), (6bR)-8-acetyl-3-(4-chlorophenyl)-6,9-dihydroxy-5,6b-dimethyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione ( 3e ), (6bR)-8-acetyl-6,9-dihydroxy-5,6b-dimethyl-3-phenyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione ( 3h ), (6bR)-3-(2-chlorophenyl)-8-[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-6,9-dihydroxy-5,6b-dimethyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione ( 4b ), and (9bR)-6-acetyl-3,7,9-trihydroxy-8,9b-dimethyl-2-[(2E)-3-phenylprop-2-enoyl]dibenzo[b,d]furan-1(9bH)-one ( 5c ) were the most potent α-glucosidase enzyme inhibitors, with IC₅₀ values of 7.0±0.24, 15.5±0.49, 7.5±0.92, 10.9±0.56, 1.5±0.62, 15.3±0.54, 19.0±1.00, and 12.3±0.53 μM, respectively.     

Eleutherinone,a novel fungitoxic naphthoquinone from Eleutherine bulbosa (Iridaceae)

The dichloromethane extract prepared from the underground parts of Eleutherine bulbosa (Miller) Urban (Iridaceae) showed strong activity in the direct bioautography assay with the phytopathogenic fungus Cladosporium sphaerospermum. This assay was used to guide the fractionation of this extract and allowed the isolation of four compounds: the new naphthoquinone eleutherinone[8-methoxy-1-methyl-1,3-dihydro-naphtho(2,3-c)furan-4,9 -dione] and the known compounds, previously isolated from this species, eleutherin [9-methoxy-1(R),3(S)-dimethyl-3,4-dihydro-1H-benzo(g)isochromene-5,10-dione], isoeleutherin [9-methoxy-1(R),3(R)-dimethyl-3,4-dihydro-1H-benzo(g)isochromene-5,10-dione], and eleutherol [4-hydroxy-5-methoxy-3(R)-methyl-3H-naphtho(2,3-c)furan-1 -one]. All quinonoid compounds showed strong antifungal activity in the bioautography assay at 100 g/spot, while eleutherol was inactive.     

Isolation of Natural Naphthoquinones from <Emphasis Type="Italic">Juglans regia</Emphasis> and In Vitro Antioxidant and Cytotoxic Studies of Naphthoquinones and the Synthetic Naphthofuran Derivatives

The naphthoquinones and their derivatives containing hydroxyl group exhibit wide range of pharmacological activities, such as antioxidant, antibacterial, antiviral, anticancer, antimalarial, and antifungal activities. In particular, the antioxidant and anticancer behaviors of these compounds continue to draw attention of researchers. In the present communication, three natural naphthoquinones—juglone, lawsone, and plumbagin—isolated from the chloroform extract of nutshells of Juglans regia Linn. and two 1,4-naphthoquinone derivatives—ethyl-5-hydroxynaphtho[ 1,2-b]furan-3-carboxylate and diethylnaphtho[1,2-b:4,3-b′]difuran-3,4-dicarboxylate—and three 5-hydroxy- 1,4-naphthoquinone derivatives—diethyl-7-hydroxynaphtho[1,2-b:4,3-b']difuran-3,4-dicarboxylate,4-ethoxycarbonyl- 7-hydroxynaphtho[1,2-b:4,3-b']difuran-3-carboxylic acid, and 7-hydroxynaphtho[1,2-b:4,3-b']difuran-3,4- dicarboxylic acid were synthesized and examined for their in vitro antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) bioassays. In addition, the cytotoxicity test using human hepatocellular liver carcinoma cell line (HepG2) was carried out for all the compounds. The 5-hydroxy-1,4-naphthoquinone derivatives displayed almost equivalent scavenging activity in DPPH assay and higher activity in ABTS assay relative to ascorbic acid. On the other hand, naphthoquinones Juglone and Plumbagin showed lesser antioxidant activity, but higher cytotoxic activity than naphthofurans except for diethyl naphtho[1,2-b:4,3-b′]difuran-3,4-dicarboxylate, which showed excellent cytotoxic activity.     

Antiviral anthraquinones from the roots of Knoxia valerianoides

Three new anthraquinones, (2S)-8-carboxy-9-hydroxy-2-(2-hydroxypropan-2-yl)-1,2-dihydroanthra[2,1-b]furan-6,11-dione (1), 1,2,3,6-tetrahydroxy-9,10-anthraquinone (2), and 1,2,3,5,6-pentahydroxy-9,10-anthraquinone (3), as well as four known 9,10-anthraquinones (4–7) and five known triterpenes (8–12), were isolated from the roots of Knoxia valerianoides. Their structures and the absolute configuration of 1 were determined through interpretation of spectroscopic data, including UV, IR, NMR and CD spectra. The isolates were evaluated for their antiviral activities, and compounds 1 and 4 showed inhibitory effects on Coxsackie virus B3 replication with IC₅₀ values of 19.24 μM and 11.11 μM, respectively. Compound 4 showed activity against influenza virus A/Hanfang/359/95 with an IC₅₀ value of 11.11 μM.     

STAT3 inhibitory activity of naphthoquinones isolated from Tabebuia avellanedae

The extract of Tabebuia avellanedae has been used as a folk medicine, and the various biological activities of T. avellanedae have been extensively studied. However, few studies have reported which natural products play a role in their biological effects. In this study, we evaluated representative naphthoquinones isolated from T. avellanedae and found that furanonaphthoquinones were the key structures required to exhibit STAT3 phosphorylation inhibitory activities. Our SAR analysis indicated that removal of a hydroxyl group enhanced the STAT3 phosphorylation inhibitory activity. In addition, the combined results of a mobility shift assay, SH2 domain binding assay, and docking simulation by Autodock 4.2.6 suggested that (S)-5-hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione (1) could directly bind to the hinge region of STAT3.     

Chemoenzymatic preparation of a biologically active naphthoquinone from Tabebuia impetiginosa using lipases or alcohol dehydrogenases

Cancer chemopreventive agent (S)-5-hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione and its counterpart (R)-acetate have been obtained through a lipase-catalyzed transesterification process in organic solvent. Candida antarctica lipase B and Pseudomonas cepacia lipase have demonstrated their potential as excellent biocatalysts for the production of enantiomerically pure compounds under mild reaction conditions. At the same time different commercially available alcohol dehydrogenases have been tested in the bioreduction of the corresponding naphthoquinone in an aqueous system. Biologically active (S)-alcohol has been isolated in enantiopure form with different conversion values depending on the biocatalyst employed and the reaction conditions.     

Synthesis and vasodilative activity of tanshinone IIA derivatives

A series of 2,2′-(substituted methylene)bis-(1,6,6-trimethyl-6,7,8,9-tetrahydrophenanthro[1,2-b]furan-10,11-dione) derivatives were synthesized by the reaction of tanshinone IIA (D₁) and aromatic aldehyde in the presence of p-TsOH. Bromination derivative of D₁ and hydrolysis product of cryptotanshinone (D₂) were also prepared in this work. Vasodilation activity in vitro of them was valuated on the contractile response of vascular thoracic aorta smooth muscle from Wistar rats for the first time. Most of them exhibited a concentration-dependent inhibition on the contractile response of norepinephrine.     

Design,synthesis and antimicrobial evaluation of novel 1-benzyl 2-butyl-4-chloroimidazole embodied 4-azafluorenones via molecular hybridization approach

A series of novel 1-benzyl-2-butyl-4-chloroimidazole embodied 4-azafluorenone hybrids, designed via molecular hybridization approach, were synthesized in very good yields using one pot condensation of 1-benzyl-2-butyl-4-chloroimidazole-5-carboxaldehyde, 1,3-indanedione, aryl/heteroaryl methyl ketones and ammonium acetate. All the synthetic derivatives were fully characterized by spectral data and evaluated for antimicrobial activity by disc diffusion method against selected bacteria and fungal strains. Among the 15 new compounds screened, 4-(1-benzyl-2-butyl-4-chloro-1H-imidazol-5-yl)-2-(furan-2-yl)-5H-indeno[1,2-b]pyridin-5-one(10k) has pronounced activity with higher zone of inhibition (ZoI) against Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Aspergillus flavus and Candida albicans. Also 4-(1-benzyl-2-butyl-4-chloro-1H-imidazol-5-yl)-2-(dibenzo[b,d]thiophen-2-yl)-5H-indeno [1,2-b]pyridin-5-one (10n) and 4-(1-benzyl-2-butyl-4-chloro-1H-imidazol-5-yl)-2-(3-tosyl-3H-inden-1-yl)-5H-indeno[1,2-b]pyridin-5-one (10o) showed selective higher inhibitory activity against Aspergillus flavus and Candida albicans. The results demonstrated potential importance of molecular hybridization in the development of 10k as potential antimicrobial agent.     

Synthesis and anti-Trypanosoma cruzi activity of derivatives from nor-lapachones and lapachones

New naphthoquinone derivatives were synthesized and assayed against bloodstream trypomastigote forms of Trypanosoma cruzi, the etiological agent of Chagas’ disease. The compounds were rationalized based on hybrid drugs and appear as important compounds against this parasite. From nor-lapachol were prepared five substituted ortho-naphthofuranquinones, a non-substituted para-naphthofuranquinone, a new oxyrane and an azide and from -lapachone a new non-substituted para-naphthofuranquinone. Other five substituted ortho-naphthofuranquinones recently designed as cytotoxic, were also evaluated. The most active compounds were the ortho naphthofuranquinones 3-(4-methoxyphenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione and 3-(3-nitrophenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione with trypanocidal activity higher than that of benznidazole, the standard drug. The compounds were rationalized based on hybrid drugs and appear as important compounds against T. cruzi. The trypanocidal activity of these substances endowed with redox properties representing a good starting point for a medicinal chemistry program aiming the chemotherapy of Chagas’ disease.     

Incrassamarin A–D: Four new 4-substituted coumarins from Calophyllum incrassatum and their biological activities

Four new 4-substituted coumarins, incrassamarin A (1), B (2), C (3) and D (4) with (7S,8S)-7,8-dihydro-5-hydroxy-7,8-dimethyl-4-propyl-2H,6H-benzo[1,2-b;5,4-b’]dipyran-2,6-dione (5), friedelin, carpachromene, amentoflavone, epiafzelechin and L-quercitrin were isolated from the barks and leaves of Calophyllum incrassatum (Guttiferae). The compounds were isolated and purified by size-exclusion recycling HPLC and column chromatographic techniques. The structures of the compounds were determined by spectroscopic means. The compounds were tested for their cytotoxic activity towards MCF-7 and A-549 cell lines and α-glucosidase enzymatic inhibitory activity. Compound (1) displayed cytotoxic activity against A-549 cell lines with IC₅₀ 87.71 μg/mL and showed inhibition towards α-glucosidase enzymatic activity with IC₅₀ 93.25 μM. This is the first report on the isolation of phytochemicals from the barks and leaves of C. incrassatum and their bioactivities.     

Design and synthesis of spirotryprostatin-inspired diketopiperazine systems from prolyl spirooxoindolethiazolidine derivatives

Based on the spirotryprostatin-A structure, we designed, synthesized, and evaluated different series of compounds belonging to the diketopiperazine structural class as potential cell cycle modulators and cytotoxic agents. Starting from the spirooxoindolthiazolidine scaffold, amide coupling with Pro derivatives and intramolecular cyclization reactions are suitable synthetic methods to generate chemically diverse diketopiperazine system, such as hexahydropyrrolo[1,2-a][1,3]thiazolo[3,2-d]pyrazine-5,10-dione (structure I), hexahydropyrrolo[1,2-a] [1,3]thiazolo[3,4-d]pyrazine-5,10-dione (structure II) and spiroindol-2-one[3,3′]hexahydro-5,10H-pyrrolo[1,2-a][1,3]thiazolo[3,4-d]pyrazine-5,10-dione (structure III). Some of these compounds, especially those who belong to the series I and II, showed interesting cytotoxic activity.     

Two new metabolites from Portulaca oleracea and their anti-inflammatory activities

Two new metabolites, identified as 6-phenylbenzofuran-4-ol, named olerabenzofuran (1), and 2-(furan-2-yl)− 6-hydroxy-1 H-inden-1-one, named oleraindenone (2), together with eight furan compounds obtained for the first time, (+)-pinoresinol (3), (-)-syringaresinol (4), (+)-diasyringaresinol (5), (+)-episyringaresinol (6), (2 S)− 1-[2-(furan-2-yl)− 2-oxoethyl]− 5-oxopyrrolidine-2-carboxylic acid (7), methyl (2 S)− 1[2-(furan-2-yl)− 2-oxoethyl]− 5-oxopyrrolidine-2-carboxylate (8), drynaran (9), and 2-furoic acid (10), were isolated from Portulaca oleracea L., and spectroscopic methods, including 1D and ²D NMR and UHPLC-ESI-QTOF/MS spectrometry techniques, were employed to determine their structures. It was suggested that both olerabenzofuran (1) and oleraindenone (2) could significantly inhibit inflammatory factor interleukin-1β (IL-1β) in RAW 264.7 cells induced by LPS.     

Design,synthesis, and biological evaluation of novel 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs in MCF-7 and MDA-MB-468 breast cancer cell lines

A series of novel 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs were designed and synthesized for developing pyrazinoindolone scaffolds as anti-breast cancer agents. Compounds 1h and 1i, having a furan-2-yl-methylamide and benzylamide group, respectively, exhibited more potent cytotoxicity in MDA-MB-468 triple-negative breast cancer (TNBC) cells than compounds possessing aliphatic groups. Compounds 2a and 2b, as (R)-enantiomers of 1h and 1i, also had inhibitory activity against MDA-MB-468 cells. Moreover, analogs (3a–b and 3d–e) bearing a benzyl group at the N-2 position showed more potent activity than gefitinib, as a potent EFGR-TK inhibitor. Especially, compound 3a exhibited selective cytotoxic activity against MDA-MB-468 cells; it also had a synergistic effect in combination with gefitinib against MDA-MB-468 cells. In addition, we confirmed that compounds 3a and 3d inhibit phosphorylation of Akt in MDA-MB-468 cells using western blot analysis. Therefore, these 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs may be helpful for investigating new anti-TNBC agents.     

Design,synthesis and in vitro anti-tuberculosis activity of benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole derivatives

A series of novel benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole hybrids (7a–j & 8a–j) have been designed and synthesized in excellent yields by Huisgen’s [3+2] cyclo addition reaction of 3-(azidomethyl)-2-methyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine (5) with various alkynes 6 in presence of copper sulphate and sodium ascorbate and their structures were confirmed by IR, ¹H NMR, ¹³C NMR and HRMS. The newly synthesized compounds 7a–j & 8a–j were evaluated for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294). Among the compounds tested, the compounds 7i and 8g displayed most potent activity with MIC value of 1.56?µg/mL with low cytotoxicity.