Hemopressin-Based pH-Sensitive Hydrogel: A Potential Bioactive Platform for Drug Delivery

Peptides with proper sequences are capable of self-assembling into well-defined nanostructures, which can subsequently grow and entangle into three-dimensional nanomatrices. In this study, hemopressin, a cannabinoid receptor-modulating peptide derived from the α-chain of hemoglobin known to self-assemble into nanofibrils, was examined for its potential applicability as a gelator. The results indicated that hemopressin’s gel formation was dependent on pH and salt concentration. Although hemopressin’s macroscopic states showed differences, its microscopic structure remained largely unchanged in which it consisted mainly of the antiparallel β-sheet conformation as confirmed by FTIR (C=O stretch peaks at 1630 and 1695 cm^–1) and CD (β-sheet peak at 195 nm). The major difference between the gel and sol states was displayed in the fibril length in which the gelation at pH 7.4 resulted in 4 μm fibrils, whereas the solution at pH 5.0 showed 800 nm fibrils. The pH-dependent sol–gel phase transition property was then utilized for the investigation of the pH-responsive release of FITC-dextran (4–40 kDa) from hemopressin fibrillary gel. Finally, the biocompatibility of the peptide was demonstrated by proliferation assay of cultured bone marrow mesenchymal stem cells. Altogether, the results suggested that hemopressin is a potentially promising candidate as a therapeutically active platform for drug delivery

Synthesis of Natural Acylphloroglucinol-Based Antifungal Compounds against <i>Cryptococcus</i> Species

Thirty-three natural-product-based acylphloroglucinol derivatives were synthesized to identify antifungal compounds against <i>Cryptococcus</i> spp. that cause the life-threatening disseminated cryptococcosis. In vitro antifungal testing showed that 17 compounds were active against <i>C. neoformans</i> ATCC 90113, <i>C. neoformans</i> H99, and <i>C. gattii</i> ATCC 32609, with minimum inhibitory concentrations (MICs) in the range 1.0–16.7 μg/mL. Analysis of the structure and antifungal activity of these compounds indicated that the 2,4-diacyl- and 2-acyl-4-alkylphloroglucinols were more active than <i>O</i>-alkyl-acylphloroglucinols. The most promising compound found was 2-methyl-1-(2,4,6-trihydroxy-3-(4-isopropylbenzyl)­phenyl)­propan-1-one (<b>11j</b>), which exhibited potent antifungal activity (MICs, 1.5–2.1 μg/mL) and low cytotoxicity against the mammalian Vero and LLC-PK1 cell lines (IC₅₀ values >50 μg/mL). This compound may serve as a template for further synthesis of new analogues with improved antifungal activity. The findings of the present work may contribute to future antifungal discovery toward pharmaceutical development of new treatments for cryptococcosis

Synthesis and Antimicrobial Evaluation of Fire Ant Venom Alkaloid Based 2‑Methyl-6-alkyl‑Δ^1,6-piperideines

The first synthesis of 2-methyl-6-pentadecyl-Δ^1,6-piperideine (<b>1</b>), a major alkaloid of the piperideine chemotype in fire ant venoms, and its analogues, 2-methyl-6-tetradecyl-Δ^1,6-piperideine (<b>2</b>) and 2-methyl-6-hexadecyl-Δ^1,6-piperideine (<b>3</b>), was achieved by a facile synthetic method starting with glutaric acid (<b>4</b>) and urea (<b>5</b>). Compound <b>1</b> showed in vitro antifungal activity against <i>Cryptococcus neoformans</i> and <i>Candida albicans</i> with IC₅₀ values of 6.6 and 12.4 μg/mL, respectively, and antibacterial activity against vancomycin-resistant <i>Enterococcus faecium</i> with an IC₅₀ value of 19.4 μg/mL, while compounds <b>2</b> and <b>3</b> were less active against these pathogens. All three compounds strongly inhibited the parasites <i>Leishmania donovani</i> promastigotes and <i>Trypanosoma brucei</i> with IC₅₀ values in the range of 5.0–6.7 and 2.7–4.0 μg/mL, respectively

Antibacterial Prenylated Acylphloroglucinols from <i>Psorothamnus fremontii</i>

Psorothatins A–C (<b>1</b>–<b>3</b>), three antibacterial prenylated acylphloroglucinol derivatives, were isolated from the native American plant <i>Psorothamnus fremontii</i>. They feature an unusual α,β-epoxyketone functionality and a β-hydroxy-α,β-unsaturated ketone structural moiety. The latter forms a pseudo-six-membered heterocyclic ring due to strong intramolecular hydrogen bonding, as indicated by the long-range proton–carbon correlations in the NMR experiments. Psorothatin C (<b>3</b>) was the most active compound against methicillin-resistant <i>Staphylococcus aureus</i> and vancomycin-resistant <i>Enterococcus faecium</i>, with IC₅₀ values in the range 1.4–8.8 μg/mL. The first total synthesis of <b>3</b> described herein permits future access to structural analogues with potentially improved antibacterial activities

Chemical Composition and Acetylcholinesterase Inhibitory Activity of Essential Oils from <i>Piper</i> Species

The essential oils (EOs) derived from aromatic plants such as <i>Piper</i> species are considered to play a role in alleviating neuronal ailments that are associated with inhibition of acetylcholinesterase (AChE). The chemical compositions of 23 EOs prepared from 16 <i>Piper</i> spp. were analyzed by both gas chromatography with a flame ionization detector (GC-FID) and gas chromatography–mass spectrometry (GC-MS). A total of 76 compounds were identified in the EOs from the leaves and stems of 19 samples, while 30 compounds were detected in the EOs from the fruits of four samples. Sesquiterpenes and phenylpropanoids were found to be rich in these EOs, of which asaricin, caryophyllene, caryophyllene oxide, isospathulenol, (+)-spathulenol, and β-bisabolene are the major constituents. The EOs from the leaves and stems of <i>Piper austrosinense</i>, <i>P. puberulum</i>, <i>P. flaviflorum</i>, <i>P. betle</i>, and <i>P. hispidimervium</i> showed strong AChE inhibitory activity with IC₅₀ values in the range of 1.51 to 13.9 mg/mL. A thin-layer chromatography (TLC) bioautography assay was employed to identify active compound(s) in the most active EO from <i>P. hispidimervium</i>. The active compound was isolated and identified as asaricin, which gave an IC₅₀ value of 0.44 ± 0.02 mg/mL against AChE, comparable to galantamine with an IC₅₀ 0.15 ± 0.01 mg/mL

Bacillusin A, an Antibacterial Macrodiolide from <i>Bacillus amyloliquefaciens</i> AP183

Bioassay-guided fractionation of the organic extracts of a <i>Bacillus amyloliquefaciens</i> strain (AP183) led to the discovery of a new macrocyclic polyene antibiotic, bacillusin A (<b>1</b>). Its structure was assigned by interpretation of NMR and MS spectroscopic data as a novel macrodiolide composed of dimeric 4-hydroxy-2-methoxy-6-alkenylbenzoic acid lactones with conjugated pentaene-hexahydroxy polyketide chains. Compound <b>1</b> showed potent antibacterial activities against methicillin-resistant <i>Staphylococcus aureus</i> and vancomycin-resistant <i>Enterococcus faecium</i> with minimum inhibitory concentrations in a range of 0.6 to 1.2 μg/mL. The biosynthetic significance of this unique class of antibiotic compounds is briefly discussed

LC-MS- and ¹H NMR Spectroscopy-Guided Identification of Antifungal Diterpenoids from <i>Sagittaria latifolia</i>

Antifungal screening of small-molecule natural product libraries showed that a column fraction (CF) derived from the plant extract of <i>Sagittaria latifolia</i> was active against the fungal pathogen <i>Cryptococcus neoformans</i>. Dereplication analysis by liquid chromatography–mass spectrometry (LC-MS) and proton nuclear magnetic resonance spectroscopy (¹H NMR) indicated the presence of new compounds in this CF. Subsequent fractionation of the plant extract resulted in the identification of two new isopimaradiene-type diterpenoids, <b>1</b> and <b>2</b>. The structures of <b>1</b> and <b>2</b> were determined by chemical methods and spectroscopic analysis as isopimara-7,15-dien-19-ol 19-<i>O</i>-α-l-arabinofuranoside and isopimara-7,15-dien-19-ol 19-<i>O</i>-α-l-(5′-acetoxy)­arabinofuranoside, respectively. Compound <b>1</b> exhibited IC₅₀ values of 3.7 and 1.8 μg/mL, respectively, against <i>C. neoformans and C. gattii</i>. Its aglycone, isopimara-7,15-dien-19-ol (<b>3</b>), resulting from acid hydrolysis of <b>1</b>, was also active against the two fungal pathogens, with IC₅₀ values of 9.2 and 6.8 μg/mL, respectively. This study demonstrates that utilization of the combined LC-MS and ¹H NMR analytical tools is an improved chemical screening approach for hit prioritization in natural product drug discovery

Chemical constituents from <i>Piper wallichii</i>

<div><p>Fifteen known compounds including four triterpenoids (<b>1</b>–<b>4</b>), one sterol (<b>5</b>), one diketopiperazine alkaloid (<b>6</b>) and nine phenolics (<b>7</b>–<b>15</b>) were isolated from the stems of <i>Piper wallichii</i>. Their structures were elucidated by means of spectroscopic analysis, and acidic hydrolysis in case of the 2-oxo-3β,19α,23-trihydroxyurs-12-en-28-oic acid β-D-glucopyranosyl ester (<b>1</b>). The structure of compound <b>1</b> was fully assigned by 1D and 2D NMR experiments for the first time. All isolates were tested for their antibacterial, antifungal, anti-inflammatory and antiplatelet aggregation bioactivities.</p></div

Biological evaluation of phytoconstituents from <i>Polygonum hydropiper</i>

<p>Fourteen compounds including vanicoside B (<b>1</b>), vanicoside F (<b>2</b>), vanicoside E (<b>3</b>) and 5,6-dehydrokawain (<b>4</b>), aniba-dimer-A (<b>5</b>), 6,6′-((1<i>α</i>,2<i>α</i>,3<i>β</i>,4<i>β</i>)-2,4-diphenylcyclobutane-1,3-diyl)bis(4-methoxy-2<i>H</i>-pyran-2-one) (<b>6</b>), (+)-ketopinoresinol (<b>7</b>), isorhamnetin (<b>8</b>), 3,7-dihydroxy-5,6-dimethoxy-flavone (<b>9</b>), isalpinin (<b>10</b>), cardamomin (<b>11</b>), pinosylvin (<b>12</b>), 2-desoxy-4-<i>epi</i>-pulchellin (<b>13</b>) and <i>β</i>-sitosterol (<b>14</b>) were isolated from dichloromethane-soluble portion of <i>Polygonum hydropiper</i>. By using Alamar blue assay, compounds <b>2</b>, <b>7</b>, <b>8</b>, <b>11</b> and <b>12</b> were found to be active against <i>Trypanosoma brucei</i> with IC₅₀ values in the range of 0.49–7.77 μg/mL. Cardamomin (<b>11</b>) had most significant activity against <i>T. brucei</i> with IC₅₀/IC₉₀ values of 0.49/0.81 μg/mL compared to the positive control DFMO (IC₅₀/IC₉₀: 3.02/8.05 μg/mL). Furthermore, in antimalarial, antimicrobial, anti-inflammatory, PPAR and cytotoxic assays, some compounds have demonstrated moderate inhibitory potentials.</p

UPLC-MS-ELSD-PDA as a Powerful Dereplication Tool to Facilitate Compound Identification from Small-Molecule Natural Product Libraries

The generation of natural product libraries containing column fractions, each with only a few small molecules, using a high-throughput, automated fractionation system, has made it possible to implement an improved dereplication strategy for selection and prioritization of leads in a natural product discovery program. Analysis of databased UPLC-MS-ELSD-PDA information of three leads from a biological screen employing the ependymoma cell line EphB2-EPD generated details on the possible structures of active compounds present. The procedure allows the rapid identification of known compounds and guides the isolation of unknown compounds of interest. Three previously known flavanone-type compounds, homoeriodictyol (<b>1</b>), hesperetin (<b>2</b>), and sterubin (<b>3</b>), were identified in a selected fraction derived from the leaves of <i>Eriodictyon angustifolium</i>. The lignan compound deoxypodophyllotoxin (<b>8</b>) was confirmed to be an active constituent in two lead fractions derived from the bark and leaves of <i>Thuja occidentalis</i>. In addition, two new but inactive labdane-type diterpenoids with an uncommon triol side chain were also identified as coexisting with deoxypodophyllotoxin in a lead fraction from the bark of <i>T. occidentalis.</i> Both diterpenoids were isolated in acetylated form, and their structures were determined as 14<i>S</i>,15-diacetoxy-13<i>R</i>-hydroxylabd-8­(17)-en-19-oic acid (<b>9</b>) and 14<i>R</i>,15-diacetoxy-13<i>S</i>-hydroxylabd-8­(17)-en-19-oic acid (<b>10</b>), respectively, by spectroscopic data interpretation and X-ray crystallography. This work demonstrates that a UPLC-MS-ELSD-PDA database produced during fractionation may be used as a powerful dereplication tool to facilitate compound identification from chromatographically tractable small-molecule natural product libraries