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).     

Antitrypanosomal activity of some pregnane glycosides isolated from Caralluma species

Pregnane glycosides previously isolated from genus Caralluma (C. Penicillata, C. tuberculata and C. russelliana) were tested for their antitrypanosomal activity. Penicilloside E showed the highest antitrypanosomal activity (IC₅₀ 1.01 μg/ml) followed by caratuberside C (IC₅₀ 1.85 μg/ml), which exhibited the highest selectivity index (SI 12.04). It was noticed that acylation is required for the antitrypanosomal activity while glycosylation at C-20 has no significant effect on the activity.     

Antiprotozoal,anticancer and antimicrobial activities of dihydroartemisinin acetal dimers and monomers

Nine dihydroartemisinin acetal dimers (6–14) with diversely functionalized linker units were synthesized and tested for in vitro antiprotozoal, anticancer and antimicrobial activity. Compounds 6, 7 and 11 [IC₅₀: 3.0–6.7 nM (D6) and 4.2–5.9 nM (W2)] were appreciably more active than artemisinin (1) [IC₅₀: 32.9 nM (D6) and 42.5 nM (W2)] against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of the malaria parasite, Plasmodium falciparum. Compounds 10, 13 and 14 displayed enhanced anticancer activity in a number of cell lines compared to the control drug, doxorubicin. The antifungal activity of 7 and 12 against Cryptococcus neoformans (IC₅₀: 0.16 and 0.55 μM, respectively) was also higher compared to the control drug, amphotericin B. The antileishmanial and antibacterial activities were marginal. A number of dihydroartemisinin acetal monomers (15–17) and a trimer (18) were isolated as byproducts from the dimer synthesis and were also tested for biological activity.     

New diterpene polyester and phenolic compounds from Pycnocycla spinosa Decne. Ex Boiss with relaxant effects on KCl-induced contraction in rat ileum

Using a bioassay-directed fractionation of Pycnocycla spinosa Decne. Ex Boiss. var. spinosa, a new polycyclic diterpenoid, 3,7,10,14,15-pentaacetyl-5-butanoyl-13,17-epoxy-8-myrsinene (1), two known compounds; vanillin (2) and isoacetovanilon (3), and a new phenolic compound, 6-(4-hydroxy-3-methoxyphenyl)-hexanoic acid (4) with inhibitory effects on KCl-induced smooth muscle contractions on the rat isolated ileum were obtained. Compound 1, the most active of the series, which exerted potent antispasmodic activity with IC₅₀ value of IC₅₀ = 0.062 ± 0.011 μM, is likely the main active ingredient of the extract. The structures of the isolated compounds were established based on ¹³C and ¹H NMR as well as 2D NMR, IR, HR-MS, and X-ray crystallographic methods.     

Anti-HIV-1 integrase diterpenoids from Dichrocephala benthamii

Five new clerodane diterpenoid dichrocephnoids A–E (1,2, 6–8) together with three known analogues were isolated from the whole herb of Dichrocephala benthamii C.B. Clarke. Their structures were elucidated on the basis of spectroscopic analyses (UV, IR, MS, 1D and 2D NMR). The relative configurations of the new compounds were established by NOESY correlations, and the absolute configuration of 1 was determined on the basis of CD methods. Dichrocephnoid A (1) possesses a very rare pentacyclic ring system with highly oxygenated functionalities. All of the isolated compounds exhibited inhibitory activity against HIV-1 integrase, however, dichrocephnoid C (6) showed the most promising inhibition of the enzyme with IC₅₀ value of 12.35 ± 1.27 μM.     

New antiprotozoal agents: Their synthesis and biological evaluations

Here we report identification of new lead compounds based on quinoline and indenoquinolines with variable side chains as antiprotozoal agents. Quinolines 32, 36 and 37 (Table 1) and indenoquinoline derivatives 14 and 23 (Table 2) inhibit the in vitro growth of the Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma brucei rhodesiense subspecies and Leishmania infantum with IC₅₀ = 0.25 μM. These five compounds have superior activity to that of the front-line drugs such as benznidazole, nifurtimox and comparable to amphotericin B. Thus these compounds constitute new ‘leads’ for further structure–activity studies as potential active antiprotozoal agents.     

New antimalarials with a triterpenic scaffold from Momordica balsamina

Bioassay-guided fractionation of the methanol extract of Momordica balsamina led to the isolation of three new cucurbitane-type triterpenoids, balsaminols C–E (1–3). Their structures were elucidated on the basis of spectroscopic methods including 2D NMR experiments (COSY, HMQC, HMBC and NOESY). Balsaminols C–E, together with ten cucurbitacins isolated from the same plant (4–13), were evaluated for their antimalarial activity against the Plasmodium falciparum chloroquine-sensitive strain 3D7 and the chloroquine-resistant clone Dd2. Most of the compounds displayed antimalarial activity. Compounds 9 and 12 revealed the highest antiplasmodial effects against both strains (IC₅₀ values: 4.6, and 7.4 μM, 3D7, respectively; 4.0, and 8.2 μM, Dd2, respectively). Structure–activity relationships are discussed. Furthermore, the preliminary toxicity toward human cells of compounds 1–5 and 9 was investigated in breast cancer cell line (MCF-7). Compounds were inactive or showed weak toxicity (IC₅₀ values >19.0).     

New secondary metabolites from Dodonaea viscosa

Bioassay guided fractionation and chemical investigation of the ethanolic extract of the aerial parts of Dodonaea viscosa Linn. from Egypt, resulted in the isolation and identification of three new compounds, including two new clerodane diterpenoids 1 and 2 and a new myo-inositol derivative 3, along with nine known compounds 4–12. The structures of the isolated compounds were elucidated using 1D and 2D NMR experiments, HRESIMS, and comparison with literature data. All isolated compounds were evaluated for their antibacterial, antifungal, antimalarial as well as antileishmanial activities. Compound 5 exhibited good antifungal activity against Cryptococcus neoformans with an IC₅₀ value of 6.11 μg/ml. Compounds 10 and 12 showed moderate antileishmanial activity against Leishmania donovani with IC₅₀ values of 16.6 and 19.06 μg/ml, respectively.     

Xanthine oxidase inhibitors isolated from Piper nudibaccatum

Two new hydroxychavicol analogs nudibaccatumin A (1) and B (2), together with twenty known compounds were isolated from the methanol extract of Piper nudibaccatum. Their structures were elucidated by extensive spectroscopic analyses (1D and 2D NMR, HRESIMS, UV, IR and polarimetry). Hydroxychavicol is a known inhibitor of xanthine oxidase (XO). In the present study, hydroxychavicol and 5 natural analogs (1–5) were evaluated for their XO inhibitory activity. Neotaiwanensol B (3) (IC₅₀ = 0.28 μM) showed a greater inhibitory effect than hydroxychavicol and allopurinol (the positive control). Two new compounds 1 and 2 showed a moderate inhibition activity with an IC₅₀ value of 62.94 μM and 70.67 μM, respectively.     

Isolation of antioxidant constituents from Combretum apiculatum subsp. apiculatum

Species of the family Combretaceae are used extensively in traditional medicine against inflammation and infections, and although antibacterial activity has been reported in non-polar extracts, further rationale for the widespread use of the Combretaceae is expected to exist. Methanol extracts of leaves of ten different Combretum species were evaluated for antioxidant activity by spraying TLC chromatograms of each leaf extract with 2,2-diphenyl-1-picrylhydrazyl (DPPH). Compounds with antioxidant activity were detected by bleaching of the purple DPPH colour. Leaf extracts of Combretum apiculatum subsp. apiculatum had the most antioxidant compounds. This species was consequently selected for phytochemical investigation. A DPPH assay-directed fractionation of the leaf extracts of C. apiculatum led to the isolation of four antioxidant compounds from the ethyl acetate and butanol soluble fractions. The structures of the compounds were determined by spectroscopic analyses (¹H-NMR, ¹³C-NMR and MS) and identified as: cardamonin (1), pinocembrin (2), quercetrin (3) and kaempferol (4). In a quantitative antioxidant assay, the more polar fractions (ethyl acetate and butanol) obtained by solvent–solvent fractionation had the highest antioxidant activity among the solvent fractions obtained from C. apiculatum, with EC₅₀ values of 3.91 ± 0.02 and 2.44 ± 0.02 μg/ml respectively. Of the four isolated compounds, quercetrin (4) and kaempferol (3) had the strongest antioxidant activity, with EC₅₀ values of 11.81 ± 85 and 47.36 ± 0.03 μM respectively. Cardamonin (1) and pinocembrin (2) did not demonstrate strong activity. L-ascorbic acid was used as standard antioxidant agent (EC₅₀ = 13.37 ± 0.20 μM or 2.35 μg/ml). The cytotoxicity of cardamonin and pinocembrin was evaluated on Vero kidney cells using the MTT (3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium bromide) assay with berberine as positive control. At concentrations higher than 50 μg/ml of cardamonin or pinocembrin, the cells were not viable. Cardamonin was more toxic (LC₅₀ = 1.97 μg/ml) than pinocembrin (LC₅₀ = 29.47 μg/ml) and even the positive control, berberine (LC₅₀ = 12.35 μg/ml).     

New coumestan and coumaronochromone derivatives from Dalbergia boehmii Taub. (Fabaceae)

Chemical investigation of leaves and heartwood of Dalbergia boehmii resulted in the isolation of two new phenolic compounds, designated dalbergestan (1) and dalbergichromone (2), along with eleven known compounds, carpachromene (3), proanthocyanidin A-2 (4); piceatannol (5); biochanin A (6); macckiain (7); homopterocarpin (8); angolensin (9); medicarpin (10); 2′,7-dihydroxy-4′,5′-dimethoxyisoflavone (11); 2′-methoxyformononetin (12); and genistein (13). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses including, IR, UV, 1D and 2D – NMR as well as HRMS data. Some of the isolated compounds were evaluated for their in vitro insulin secretion activity on isolated mice islets, leishmanicidal activity against L. major (DESTO) promastigotes and in vitro cytotoxicity on MCF-7 cell lines. All tested compounds were inactive on glucose-stimulated insulin secretion at stimulatory glucose (20.0 mM) from MIN6 cells. Compounds 3 (IC₅₀, 70.0 μg/ml), 6 (IC₅₀, 60.3 μg/ml), 7 (IC₅₀, 86.5 μg/ml) and 13 (IC₅₀, 62.6 μg/ml) exhibited low leishmanicidal activity while compound 12 (IC₅₀, 56.8 μg/ml) displayed a moderate activity. Compounds 3 and 5 were found to be active against MCF-7 at 50 μM with IC₅₀ value 33.2 ± 3.79 μg/ml and 42.64 ± 5.05 μg/ml respectively.     

Aspernolides F and G,new butyrolactones from the endophytic fungus Aspergillus terreus

Two new butyrolactones: aspernolides F (6) and G (7), together with three stigmasterol derivatives: (22E,24R)-stigmasta-5,7,22-trien-3-β-ol (1), stigmast-4-ene-3-one (2), and stigmasta-4,6,8(14), 22-tetraen-3-one (3), two meroterpenoids: terretonin A (4) and terretonin (5), and a butyrolactone derivative: butyrolactone VI (8) have been isolated from the endophytic fungus Aspergillus terreus isolated from the roots of Carthamus lanatus (Asteraceae). Their structures were determined by spectroscopic means (1D, 2D NMR, and HRESIMS), as well as optical rotation measurement and comparison with literature data. The isolated compounds were evaluated for their anti-microbial, anti-malarial, anti-leishmanial, and cytotoxic activities. Compound 1 displayed a potent activity against MRSA and C. neoformans with IC₅₀ values of 0.96 μg/mL and 4.38 μg/mL, respectively compared to ciprofloxacin (IC₅₀ 0.07 μg/mL) and amphotericin B (IC₅₀ 0.34 μg/mL), respectively. While, 6 showed good activity against C. neoformans (IC₅₀ 5.19 μg/mL) and mild activity against MRSA (IC₅₀ 6.39 μg/mL). Moreover, 1 and 2 exhibited very good anti-leishmanial activity towards L. donovani with IC₅₀ values of 4.61 and 6.31 μg/mL, respectively and IC₉₀ values of 6.02 and 16.71 μg/mL, respectively.     

Isolation of antiplasmodial anthraquinones from Kniphofia ensifolia,and synthesis and structure–activity relationships of related compounds

Bioassay-guided separation of the South African plant Kniphofia ensifolia for antiplasmodial activity led to the isolation of two new anthraquinones, named kniphofiones A and B (3 and 4), together with three known bioactive anthraquinone monomers (1, 2 and 5), and four known bisanthraquinones (6–9). The structures of the two new compounds were elucidated based on analyses of their 1D and 2D NMR spectra and mass spectrometric data. The dimeric compounds 6 and 7 displayed the strongest antiplasmodial activity among all the isolated compounds, with IC₅₀ values of 0.4 ± 0.1 and 0.2 ± 0.1 μM, respectively. The two new compounds displayed modest activities, with IC₅₀ values of 26 ± 4 and 9 ± 1 μM, respectively. Due to the synthetic accessibility of the new compounds and the increased activity shown by the dimeric compounds, a structure–activity relationship study was conducted. As a result, one analogue of kniphofione B (4), the caffeic acid derivative of aloe-emodin, was found to have the highest activity among all the aloe-emodin derivatives, with an IC₅₀ value of 1.3 ± 0.2 μM.     

Pumilanol,an antiprotozoal isoflavanol from Tephrosia pumila

A novel isoflavan-4-ol (pumilanol), (rel)-3β-(2′-hydroxy-4′,5′-methylenedioxyphenyl)-6-methoxy-4α,7-dihydroxybenzo-3,4-dihydropyran (1) and two known flavonoids, tephrinone (2) and rotenone (3) together with lupeol and stigmasterol were isolated from the roots of Tephrosia pumila (Fabaceae) from a collection made in Andhra Pradesh, India. The structures of the compounds were determined by MS, 1D and 2D-NMR spectral analysis. Pumilanol (1) exhibited significant antiprotozoal activity against T. b. rhodensiense, T. cruzi and L. donovani with IC₅₀ of 3.7, 3.35 and 17.2 μg/mL, respectively, but displayed high toxicity towards L-6 (IC₅₀ of 17.12 μg/mL) rat skeletal myoblasts.     

Cytotoxic acridone and indoloquinazoline alkaloids from Zanthoxylum poggei

Two new alkaloids, poggeicridone (1) and 2-methoxy-7,8- dehydroruteacarpine (6), together with nine known compounds, were isolated from the dichloromethane (DCM) extract of the bark of Zanthoxylum poggei (Engl.) P. G. Waterman. The structures of all compounds were determined by comprehensive spectroscopic analyses (1D and 2D NMR and EI- and ESI⿿MS). Compounds 5-9 exhibited strong suppressive effects on the phagocytosis response upon activation with serum opsonized zymosan in the in vitro oxidative burst studies using whole blood. The IC₅₀ values were in the range of 12.0⿿25.9 μM. These compounds displayed a moderate level of cytotoxic activity against the human Caucasian prostate adenocarcinoma cell line PC-3, with IC₅₀ values of 15.8 and 22.1 μM (the IC₅₀ value of the positive control standard doxorubicin was IC₅₀ 0.9 μM). All isolated compounds were also tested against plant pathogenic bacteria, fungi and oomycetes using the paper disk agar diffusion assay, resulting in no significant activities (MICs > 1 mg/mL).     

Constituents of Nelumbo nucifera leaves and their antimalarial and antifungal activity

From the leaves of Nelumbo nucifera (an aquatic plant), one new compound, 24(R)-ethylcholest-6-ene-5α-ol-3-O-β-d-glucopyranoside (1), along with 11 known metabolites (2–12), were isolated and identified by spectroscopic methods including 1D- and 2D NMR. Antifungal activity for (R)-roemerine (3) (IC₅₀/MIC = 4.5/10 μg/mL against Candida albicans) and antimalarial activity for (R)-roemerine (3) and N-methylasimilobine (5) (IC₅₀ = 0.2 and 4.8 μg/mL for the D6 clone, respectively, and 0.4 and 4.8 μg/mL for the W2 clone, respectively) was observed. None of the compounds were cytotoxic to Vero cells up to a concentration of 23.8 μg/mL. NMR data for 10-eicosanol (7) and 7,11,15-trimethyl-2-hexadecanone (10) are presented for the first time. An analysis of the structure–activity relationship shows that the substituents in position C-1 and C-2 of aporphine alkaloids are crucial for the antimalarial activity.     

Rational design,synthesis and biological evaluation of 1,3,4-oxadiazole pyrimidine derivatives as novel pyruvate dehydrogenase complex E1 inhibitors

On the basis of previous study on 2-methylpyrimidine-4-ylamine derivatives I, further synthetic optimization was done to find potent PDHc-E1 inhibitors with antibacterial activity. Three series of novel pyrimidine derivatives 6, 11 and 14 were designed and synthesized as potential Escherichia coli PDHc-E1 inhibitors by introducing 1,3,4-oxadiazole-thioether, 2,4-disubstituted-1,3-thiazole or 1,2,4-triazol-4-amine-thioether moiety into lead structure I, respectively. Most of 6, 11 and 14 exhibited good inhibitory activity against E. coli PHDc-E1 (IC₅₀ 0.97–19.21 μM) and obvious inhibitory activity against cyanobacteria (EC₅₀ 0.83–9.86 μM). Their inhibitory activities were much higher than that of lead structure I. 11 showed more potent inhibitory activity against both E. coli PDHc-E1 (IC₅₀ < 6.62 μM) and cyanobacteria (EC₅₀ < 1.63 μM) than that of 6, 14 or lead compound I. The most effective compound 11d with good enzyme-selectivity exhibited most powerful inhibitory potency against E. coli PDHc-E1 (IC₅₀ = 0.97 μM) and cyanobacteria (EC₅₀ = 0.83 μM). The possible interactions of the important residues of PDHc-E1 with title compounds were studied by molecular docking, site-directed mutagenesis, and enzymatic assays. The results indicated that 11d had more potent inhibitory activity than that of 14d or I due to its 1,3,4-oxadiazole moiety with more binding position and stronger interaction with Lsy392 and His106 at active site of E. coli PDHc-E1.     

A lanostane aldehyde from Momordica charantia

A new lanostane aldehyde, charantal (1), was isolated from the ethanolic leaf extract of Momordica charantia together with the known compound, 2,4-bis(2-phenylpropan-2-yl)phenol (2). The structure of compound 1 was elucidated by extensive 1D and 2D NMR and MS experiments. Compound 2 displayed a moderately strong antitubercular activity against Mycobacterium tuberculosis H₃₇Rv (MIC = 14 μg/mL) according to the MABA susceptibility assay.     

Bioactive 2-pyrone metabolites from an endophytic Phomopsis asparagi SWUKJ5.2020 of Kadsura angustifolia

Five new 2-pyrone metabolites, phomaspyrones A–E (1–5) along with three known compounds, macommelin-8,9-diol (6), macommelin-9-ol (7), and macommelin (8), were isolated from the culture broth of an endophytic fungus Phomopsis asparagi SWUKJ5.2020 of medicinal plant Kadsura angustifolia by sequentially purification over silica gel, Sephadex LH-20 column chromatography and preparative HPLC. Their structures were elucidated on the basis of spectroscopic analysis, including two-dimensional (2D) NMR and HRMS (ESI-TOF) data. Among them, compounds 3–5 exhibited notable cytotoxicity against HL-60 and K562 cells with IC₅₀ values of below 10 μg/mL better than those of the other isolated metabolites (IC₅₀ = 10.6–26.6 μg/mL). The results showed that the keto or hemiketal functionality might play an important role in cytotoxic activity of this class of compounds.     

Identification of new potent inhibitor of aldose reductase from Ocimum basilicum

Recent efforts to develop cure for chronic diabetic complications have led to the discovery of potent inhibitors against aldose reductase (AKR1B1, EC 1.1.1.21) whose role in diabetes is well-evident. In the present work, two new natural products were isolated from the ariel part of Ocimum basilicum; 7-(3-hydroxypropyl)-3-methyl-8-β-O-d-glucoside-2H-chromen-2-one (1) and E-4-(6′-hydroxyhex-3′-en-1-yl)phenyl propionate (2) and confirmed their structures with different spectroscopic techniques including NMR spectroscopy etc. The isolated compounds (1, 2) were evaluated for in vitro inhibitory activity against aldose reductase (AKR1B1) and aldehyde reductase (AKR1A1). The natural product (1) showed better inhibitory activity for AKR1B1 with IC₅₀ value of 2.095 ± 0.77 µM compare to standard sorbinil (IC₅₀ = 3.14 ± 0.02 µM). Moreover, the compound (1) also showed multifolds higher activity (IC₅₀ = 0.783 ± 0.07 µM) against AKR1A1 as compared to standard valproic acid (IC₅₀ = 57.4 ± 0.89 µM). However, the natural product (2) showed slightly lower activity for AKR1B1 (IC₅₀ = 4.324 ± 1.25 µM). Moreover, the molecular docking studies of the potent inhibitors were also performed to identify the putative binding modes within the active site of aldose/aldehyde reductases.