Synthesis of antimalarial amide analogues based on the plant serrulatane diterpenoid 3,7,8-trihydroxyserrulat-14-en-19-oic acid

A plant-derived natural product scaffold, 3,7,8-trihydroxyserrulat-14-en-19-oic acid (1) was isolated in high yield from the aerial parts of the endemic Australian desert plant Eremophila microtheca. This scaffold (1) was subsequently used in the generation of a series of new amide analogues via a one-pot mixed anhydride amidation using pivaloyl chloride. The structures of all analogues were characterized using MS, NMR, and UV data. The major serrulatane natural products (1–3), isolated from the plant extract, and all amide analogues (6–15) together with several pivaloylated derivatives of 3,7,8-trihydroxyserrulat-14-en-19-oic acid (16–18) were evaluated for their antimalarial activity against 3D7 (chloroquine sensitive) and Dd2 (chloroquine resistant) Plasmodium falciparum strains, and preliminary cytotoxicity data were also acquired using the human embryonic kidney cell line HEK293. The natural product scaffold (1) did not display any antimalarial activity at 10 µM. Replacing the carboxylic acid of 1 with various amides resulted in moderate activity against the P. falciparum 3D7 strain with IC₅₀ values ranging from 1.25 to 5.65 µM.     

Antimicrobial compounds from Eremophila serrulata

We report a search for antimicrobial compounds in the Australian plant Eremophila serrulata. Bioassay directed fractionation of a diethyl ether extract prepared from the leaves of E. serrulata led to the isolation of two compounds, an omicron-naphthoquinone, 9-methyl-3-(4-methyl-3-pentenyl)-2,3-dihydronaphtho[1,8-bc]pyran-7,8-dione (2), and a serrulatane diterpenoid, 20-acetoxy-8-hydroxyserrulat-14-en-19-oic acid (3). Two other known serrulatane-type diterpenoids, 8,20-dihydroxyserrulat-14-en-19-oic acid (4) and 8,20-diacetoxyserrulat-14-en-19-oic acid (5) were also isolated. None of these compounds had previously been tested for antimicrobial activity. Compounds 2-5 showed antimicrobial activity against Staphylococcus aureus (ATCC 29213) with minimum inhibitory concentrations (MICs) ranging from 15.6 to 250mug/mL. Compound 2 was the most active with an MIC of 15.6mug/mL and a minimum bactericidal concentration (MBC) of 125mug/mL. This compound also showed antimicrobial activity against other Gram-positive bacteria including Streptococcus pyogenes, and Streptococcus pneumoniae. No activity was observed for this compound against all Gram-negative bacteria tested.     

Triterpenes from the roots of Lantana montevidensis with antiprotozoal activity

Bioassay guided fractionation of the roots of Lantana montevidensis (Verbenaceae) has resulted in the isolation and identification of three new triterpenoids; 13β-hydroxy-3-oxo-olean-11-en-28-oic acid (1), 12β,13β-dihydroxyolean-3-oxo-28-oic acid (2) and 12β,13β,22β-trihydroxyolean-3-oxo-28-oic acid (3) in addition to nine known compounds: oleanonic acid (4), oleanolic acid (5), 3β,25β-dihydroxy-olean-12-en-28-oic acid (6), lantadene A (7), 19α-hydroxy-3-oxo-olean-12-en-28-oic acid (8) pomolic acid (9), camaric acid (10) together with β-sitosterol (11) and β-sitosterol-3-O-β-d-glucoside (12). The structures of the isolated metabolites were elucidated based on comprehensive 1D and 2D NMR spectroscopic data as well as HR-ESI–MS. The extracts and the isolated metabolites were evaluated for their antiprotozoal and antimicrobial activities. Compound 2 showed antibacterial activity against Staphylococcus aureus and methicillin resistant S. aureus with IC₅₀ values against both organisms of 2.1 μM and compound 10 showed activity against same organisms with IC₅₀ values 8.74 and 8.09 μM, respectively, compared to the positive control ciprofloxacin (IC₅₀ = 0.3 μM against S. aureus and MRSA). Compounds 1, 4, 5, 6, and 10 showed moderate antileishmanial activity with IC₅₀ values ranging between (2.54–14.95 μM) and IC₉₀ values ranging between (11.90–19.47 μM), using pentamidine as a control (IC₅₀ values 2.09 ≥ 16.8 μM) and IC₉₀ values ranging between (4.72 ≥ 16.8 μM). These compounds also showed highly potent antitrypanosomal activity with IC₅₀ values ranging between (0.39–7.12 μM) and IC₉₀ values ranging between (1.91–10.51 μM), which are more efficient than the DFMO, the antitrypanosomal drug employed as positive control (IC₅₀ and IC₉₀values 11.82 and 30.82 μM).     

Biotransformation of ent-pimaradienoic acid by cell cultures of Aspergillus niger

Microbial transformation stands out among the many possible semi-synthetic strategies employed to increase the variety of chemical structures that can be applied in the search for novel bioactive compounds. In this paper we obtained ent-pimaradienoic acid (1, PA, ent-pimara-8(14),15-dien-19-oic acid) derivatives by fungal biotransformation using Aspergillus niger strains. To assess the ability of such compounds to inhibit vascular smooth muscle contraction, we also investigated their spasmolytic effect, along with another five PA derivatives previously obtained in our laboratory, on aortic rings isolated from male Wistar rats. The microbial transformation experiments were conducted at 30 °C using submerged shaken liquid culture (120 rpm) for 10 days. One known compound, 7α-hydroxy ent-pimara-8(14),15-dien-19-oic acid (2), and three new derivatives, 1β-hydroxy ent-pimara-6,8(14),15-trien-19-oic acid (3), 1α,6β,14β-trihydroxy ent-pimara-7,15-dien-19-oic acid (4), and 1α,6β,7α,11α-tetrahydroxy ent-pimara-8(14),15-dien-19-oic acid (5), were isolated and identified on the basis of spectroscopic analyses and computational studies. The compounds obtained through biotransformation (2–5) did not display a significant antispasmodic activity (values ranging from 0% to 16.8% of inhibition); however the previously obtained diterpene, methyl 7α-hydroxy ent-pimara-8(14),15-dien-19-oate (8), showed to be very effective (82.5% of inhibition). In addition, our biological results highlight the importance to study the antispasmodic potential of a large number of novel diterpenes, to conduct further structure–activity relationship investigations.     

New derivatives of ursolic acid through the biotransformation by Bacillus megaterium CGMCC 1.1741 as inhibitors on nitric oxide production

Microbial transformation of ursolic acid (1) by Bacillus megaterium CGMCC 1.1741 was investigated and yielded five metabolites identified as 3-oxo-urs-12-en-28-oic acid (2); 1β,11α-dihydroxy-3-oxo-urs-12-en-28-oic acid (3); 1β-hydroxy-3-oxo-urs-12-en-28, 13-lactoe (4); 1β,3β, 11α-trihydroxyurs-12-en-28-oic acid (5) and 1β,11α-dihydroxy-3-oxo-urs-12-en-28-O-β-d-glucopyranoside (6). Metabolites 3, 4, 5 and 6 were new natural products. Their nitric oxide (NO) production inhibitory activity was assessed in lipopolysaccharide (LPS) – stimulated RAW 264.7 cells. Compounds 3 and 4 exhibited significant activities with the IC₅₀ values of 1.243 and 1.711 μM, respectively. A primary structure-activity relationship was also discussed.     

Four new triterpenoidal saponins from Ilex cornuta and their cytotoxic activities

Four new triterpenoidal saponins (1–4), oleanolic acid 3β-O-α-l-arabinopyranosyl-(1 → 2)-β-d-glucuronopyranoside-6-O-butyl ester (1), oleanolic acid 3β-O-[α-l-arabinopyranosyl-(1 → 2)-β-d-glucuronopyranoside-6-O-butyl ester]-28-O-β-d-glucopyranoside (2), 19α-hydroxy oleanolic acid 3β-O-β-d-glucuronopyranoside-6-O-methyl ester (3), and 19α-hydroxy urs-12-en-28-oic acid 3β-O-α-l-arabinopyranosyl-(1 → 2)-β-d-glucuronopyranoside-6-O-methyl ester (4) were isolated from the roots of Ilex cornuta. Their structures were determined by means of extensive spectroscopic analyses (IR, ESIMS, HRESIMS, 1D and 2D NMR). Compounds 1–9 were tested for their cytotoxic activities by MTT assay, and 1, 3, 5 and 6 showed moderate cytotoxic activities against HeLa, SMMC-7721, and HL-60 human tumor cell lines.     

Bioactivity-guided isolation of cytotoxic triterpenoids from the trunk of Berberis koreana

A bioassay-guided fractionation and chemical investigation of the trunk of Berberis koreana resulted in the isolation and characterization of two new triterpenoids, 23-trans-p-coumaroyloxy-2α,3α-dihydroxyolean-12-en-28-oic acid (1), and 23-cis-p-coumaroyloxy-2α,3α-dihydroxyolean-12-en-28-oic acid (2), along with seven known triterpenoids (3–9). The structures of the new compounds were determined on the basis of spectroscopic analyses including 2D NMR. The cytotoxic activities of the triterpenes (1–9) were evaluated by determining their inhibitory effects on human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15) using the SRB assay. Compounds 5 and 6 showed potent cytotoxicity against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines (IC₅₀ (5): 4.37, 7.04, 9.72, and 5.83 μM, and IC₅₀ (6): 5.57, 7.84, 13.29, and 5.61 μM, respectively).     

Synthesis and biological evaluation of 5-aryloxypyrazole derivatives bearing a rhodanine-3-aromatic acid as potential antimicrobial agents

Three novel series of 5-aryloxypyrazole derivatives have been synthesized and tested for their antibacterial activity. The majority of the synthesized compounds showed potent inhibitory activity against Gram-positive bacteria Staphylococcus aureus 4220, especially against the strains of multidrug-resistant clinical isolates (MRSA3167/3506 and QRSA3505/3519). Among which compounds IIIb, IIIg and IIIm showed the most potent levels of activity (MIC = 1 μg/mL) against the multidrug-resistant strains. And cytotoxic activity assay showed that the compounds tested did not affect cell viability on the Human cervical (HeLa) cells at their MICs. The current study therefore suggests that 5-aryloxypyrazoles bearing a rhodanine-3-aromatic acid moiety are promising scaffolds for the development of novel Gram-positive antibacterial agents.     

Acetylenic 2-phenylethylamides and new isobutylamides from Acmella oleracea (L.) R. K. Jansen,a Brazilian spice with larvicidal activity on Aedes aegypti

Ethanol extract obtained from dried leaves of Acmella oleracea afforded after a liquid/liquid partition procedure a larvicidal hexane fraction (LC₅₀ = 145.6 ppm) and a non larvicidal dichloromethane one. From the inactive fraction, three amides were identified, two new structures, named deca-6,9-dihydroxy-(2E,7E)-dienoic acid isobutylamide (1), deca-8,9-dihydroxy-(2E,6Z)-dienoic acid isobutylamide (2) and the known nona-2,3-dihydroxy-6,8-diynoic acid 2-phenylethylamide (3). Bioassay-guided chromatographic fractionation of the hexane partition led to the identification of an amide mixture, nona-(2Z)-en-6,8-diynoic acid 2-phenylethylamide (4) and deca-(2Z)-en-6,8-diynoic acid 2-phenylethlylamide (5). This mixture was active against Aedes aegypti larvae at LC₅₀ = 7.6 ppm. Low toxicity of crude extracts and derived fractions on Artemia salina nauplies showed the possibility of using them to control the A. aegypti mosquito larvae. This is the first report on larvicidal activity of acetylenic 2-phenylethylamides and their identification in A. oleracea leaves.     

New 19α-hydroxyursane-type triterpenes from the leaves of Meyna spinosa (= Vangueria spinosa), Rubiaceae

Two new 19α-hydroxyursane-type triterpenes, 2α,3α,19α,24,28-pentahydroxyurs-12-ene (1) and meyanthic acid, 3β-acetoxy-2β,19α,23-trihydroxyurs-12-en-28-oic acid (2) along with one new aliphatic ester, myricyl pentadecanoate (3) and five known compounds, 19α-hydroxyasiatic acid (4), oleanolic acid (5), myricyl alcohol (6), β-sitosterol (7) and its glycoside (8) were isolated from the methanolic leaf extract of Meyna spinosa Roxb. ex Link (= Vangueria spinosa Roxb., Rubiaceae). The structures of the new compounds were elucidated on the basis of extensive spectroscopic (including 2D NMR) analysis and comparison with literature. Except oleanolic acid, isolation of known compounds was reported for the first time from this plant.     

A new ursane and a new oleanane triterpene acids from the whole plant of Spermacoce latifolia

A phytochemical study on the whole plant of Spermacoce latifolia led to the isolation of a new ursane triterpene acid, 3β,6β,23-trihydroxy-urs-12,20(30)-dien-28-oic acid (1), and a new oleanane triterpene acid, 3β,6β,29-trihydroxy-olean-12-en-28-oic acid (2), together with seven known triterpenic acids (3–9). Their structures were established on the basis of detailed spectroscopic analysis, including one- and two-dimensional NMR, ESI–MS and HR–ESI–MS techniques. All the compounds were isolated from S. latifolia for the first time. Compounds 3, 5, 6 and 9 were found to show in vitro growth inhibitory activity against three assayed human cancer cell lines MCF-7, NCI-H460 and HepG-2 with IC₅₀ values from 9.53 to 80.20 mM. Compounds 1 and 3–9 were further revealed to show significantly in vitro α-glucosidase inhibitory activity with IC₅₀ values from 0.009 to 0.422 mM, most of which were more potent than the reference compound acarbose (IC₅₀ 0.409 mM).     

Chemotaxonomic implications of the absence of sesquiterpene lactones in Grazielia multifida (DC.) R.M.King & H.Rob. (Asteraceae)

The phytochemical investigation of Grazielia multifida aerial parts yielded eight compounds, including four ent-kaurenic acid diterpenes derivatives, 15-tiglinoyloxy-ent-kaur-16-en-19-oic acid (1), 15-hydroxy-ent-kaur-16-en-19-oic acid (2), 17-hydroxy-ent-kaur-15-en-19-oic acid (3) and 15-isovaleroyloxy-ent-kaur-16-en-19-oic acid (4), one amino acid, tryptophan (5), and three flavonoids, eupafolin (6), guaijaverin (7) and quercitrin (8). The structures of the isolated compounds were established based on analysis of their spectroscopic data and comparison with literature. All the compounds were isolated from this species for the first time. The chemotaxonomic significance of the absence of sesquiterpene lactones in G. multifida has also been summarized.     

A new δ-tocotrienolic acid derivative and other constituents from the cones of Cedrus atlantica and their in vitro antimicrobial activity

The phytochemical and antimicrobial properties of the cones of Cedrus atlantica (Endl) Manetti ex Carrière were investigated. Two new compounds (1,2) and nineteen known compounds (3–21) were isolated. Their structures were established by mass spectrometry (HRESIMS), 1D, 2D NMR and by comparison with literature data. Antimicrobial activity of hydromethanolic extract against a panel of 22 bacteria and yeasts showed an interesting antimicrobial activity. All compound purified from this extract were tested against S. aureus by bioautography. MIC values of the most active compounds were determined using a serial dilution technique. The results showed strong antibacterial activity of the abietane diterpenes 10, 11, 14, 15, 16 and 17. Dehydroabietic acid (17) was the most potent against Enterococcus faecalis (MIC = 15.1 = μg/mL), a multi-resistant commensal bacterium which can cause the fatal infections in humans.     

Synthesis and antimicrobial activity of novel amphiphilic aromatic amino alcohols

We report in this work the preparation and in vitro antimicrobial evaluation of novel amphiphilic aromatic amino alcohols synthesized by reductive amination of 4-alkyloxybenzaldehyde with 2-amino-2-hydroxymethyl-propane-1,3-diol. The antibacterial activity was determined against four standard strains (Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa) and 21 clinical isolates of methicillin-resistant Staphylococcus aureus. The antifungal activity was evaluated against four yeast (Candida albicans, Candida tropicalis, Candida glabrata and Candida parapsilosis). The results obtained showed a strong positive correlation between the lipophilicity and the antibiotic activity of the tested compounds. The best activities were obtained against the Gram-positive bacteria (MIC = 2–16 μg ml^?1) for the five compounds bearing longer alkyl chains (4c–g; 8–14 carbons), which were also the most active against Candida (MIC = 2–64 μg ml^?1). Compound 4e exhibited the highest levels of inhibitory activity (MIC = 2–16 μg ml^?1) against clinical isolates of MRSA. A concentration of twice the MIC resulted in bactericidal activity of 4d against 19 of the 21 clinical isolates.     

Psammaplysin F: A unique inhibitor of bacterial chromosomal partitioning

Described is the antibiotic activity of a marine natural product. Psammaplysin F (1) inhibited the growth of four Gram-positive strains by >80% at 50 μM, and the amine at position C-20 is responsible for the observed antibacterial activity. When tested against two strains of methicillin resistant Staphylococcus aureus (MRSA), the minimum inhibitory concentrations (MICs) for psammaplysin F (40–80 μM) were similar to the structurally-related alkaloid psammaplysin H (2). Psammaplysin F (1) increased membrane permeability by two to four-fold compared to psammaplysin H (2) or control-treated bacteria, respectively. Unlike psammaplysin H (2), we show that psammaplysin F (1) inhibits equal partitioning of DNA into each daughter cell, suggesting that this natural product is a unique prokaryotic cell division inhibitor.     

Design,synthesis and biological activity evaluation of novel 2,6-difluorobenzamide derivatives through FtsZ inhibition

Novel series of 3-substituted 2,6-difluorobenzamide derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their in vitro antibacterial activity against various phenotype of Gram-positive and Gram-negative bacteria, and their cell division inhibitory activity against three representative strains. As a result, 3-chloroalkoxy derivative 7, 3-bromoalkoxy derivative 12 and 3-alkyloxy derivative 17 were found to exhibit the best antibacterial activity against Bacillus subtilis with MICs of 0.25–1 μg/mL, and good activity (MIC < 10 μg/mL) against both susceptible and resistant Staphylococcus aureus. Additionally, all the three compounds displayed potent cell division inhibitory activity with MIC values of below 1 μg/mL against Bacillus subtilis and Staphylococcus aureus.     

Antiplatelet aggregation triterpene saponins from the leaves of Ilex kudingcha

Two new ursane-type triterpene saponins, 3-O-β-d-glucopyranosyl(1 → 3)-[α-l-rhamnopyranosyl(1 → 2)]-α-l-arabinopyranosylurs-12,19(29)-dien-28-oic acid 28-O-α-l-rhamnopyranosyl(1 → 2)-β-d-glucopyranosyl ester (1) and 3-O-β-d-glucopyranosyl(1 → 3)-[α-l-rhamnopyranosyl(1 → 2)]-α-l-arabinopyranosyl-19α,20α-dihydroxyurs-12-en-28-oic acid 28-O-α-l-rhamnopyranosyl(1 → 2)-β-d-glucopyranosyl ester (2), along with thirteen known triterpene saponins were isolated from the n-BuOH part of the MeOH extraction of the leaves of Ilex kudingcha C.J. Tseng (also called “Ku-Ding-Cha”). The structures of new compounds were elucidated on the basis of detailed spectroscopic analysis, including HR-ESI-TOF-MS, 1D and 2D-NMR experiments, and by acid hydrolysis. All the compounds were screened for antiplatelet aggregation activity in vitro, and compounds 1, 2, 3, 7, 12 and 15 showed significant inhibition of platelet aggregation induced by ADP (5 μM) with IC₅₀ values of 14.7 ± 3.7, 11.3 ± 2.5, 17.4 ± 4.6, 20.5 ± 3.1, 8.1 ± 1.5 and 18.9 ± 4.2 μM, respectively.     

Antibacterially active phenolic lipid derivatives from Comarum salesovianum (Steph.) Aschers. et Gr.

The antibacterial activity-guided purification of the dichloromethane fraction of the aerial parts of Comarum salesovianum (Steph.) Aschers.et Gr. led to the isolation and elucidation of three phenolic lipid derivatives: 6-(non-8-enyl) salicylic acid (1), 6-nonyl salicylic acid (2) and 3-(non-8-enyl) phenol (3), which were found for the first time in the natural source. The equal mixture of compounds 1 and 2 exhibited potent inhibitory activity against all tested Gram-positive bacterial strains (Enterococcus faecalis, Micrococcus luteus, Staphylococcus epidermidis and Staphylococcus aureus) with inhibitory zones of 12.2–22.1 mm, whereas each single compound showed weaker activity than the mixture of 1 and 2. However, compound 3 strongly inhibited (29.9 ± 1.8) the growth of M. luteus. The presence of salicylic acid with the unsaturated aliphatic side chain is essential for the antibacterial activity strength of phenolic lipid molecules.     

A new complex triterpenoid saponin from Samanea saman with haemolytic activity and adjuvant effect

A new complex triterpenoid saponin was isolated from the stem bark of Samanea saman by using chromatographic methods. Its structure was established as 3-[(2-O-β-d-glucopyranosyl-β-d-glucopyranosyl)oxy]-2,23-dihydroxy-(2β,3β,4α)-olean-12-en-28-oic acid O-β-d-glucopyranosyl-(1 → 3)-O-[O-β-d-glucopyranosyl-(1 → 4)]-O-6-deoxy-α-l-mannopyranosyl-(1 → 2)-6-O-[4-O-[(2E,6S)-2,6-dimethyl-1-oxo-2,7-octadienyl]-6-deoxy-α-l-mannopyranosyl)oxy]-β-d-glucopyranosyl ester (1). Structural elucidation was performed using detailed analyses of ¹H and ¹³C NMR spectra including 2D NMR spectroscopic techniques and chemical conversions. The haemolytic activity of the saponin was evaluated using in vitro assays, and its adjuvant potential on the cellular immune response against ovalbumin antigen was investigated using in vivo models.     

Ent-kauren-19-oic acid derivatives from the stem bark of Croton pseudopulchellus Pax

Two new ent-kauren-19-oic acid derivatives, ent-14S*-hydroxykaur-16-en-19-oic acid and ent-14S*,17-dihydroxykaur-15-en-19-oic acid together with eleven known compounds ent-kaur-16-en-19-oic acid, ent-kaur-16-en-19-al, ent-12β-hydroxykaur-16-en-19-oic acid, ent-12β-acetoxykaur-16-en-19-oic acid, 8R,13R-epoxylabd-14-ene, eudesm-4(15)-ene-1β,6α-diol, (?)-7-epivaleran-4-one, germacra-4(15), 5E,10(14)-trien-9β-ol, acetyl aleuritolic acid, β-amyrin, and stigmasterol were isolated from the stem bark of Croton pseudopulchellus (Euphorbiaceae). Structures were determined using spectroscopic techniques. Ent-14S*-hydroxykaur-16-en-19-oic acid, ent-kaur-16-en-19-oic acid, ent-12β-hydroxykaur-16-en-19-oic acid, ent-12β-acetoxykaur-16-en-19-oic acid and 8R,13R-epoxylabd-14-ene were tested for their effects on Semliki Forest virus replication and for cytotoxicity against human liver tumour cells (Huh-7 strain) but were found to be inactive. Ent-kaur-16-en-19-oic acid, the major constituent, showed weak activity against the Plasmodium falciparum (CQS) D10 strain.