8 research outputs found
Discovery of a Membrane-Active, Ring-Modified Histidine Containing Ultrashort Amphiphilic Peptide That Exhibits Potent Inhibition of <i>Cryptococcus neoformans</i>
The new structural classes of ultrashort
peptides that exhibit
potent microbicidal action have potential as future drugs. Herein,
we report that C-2 arylated histidines containing tripeptides HisÂ(2-Ar)-Trp-HisÂ(2-Ar)
exhibit potent antifungal activity against <i>Cryptococcus neoformans</i> with high selectivity. The most potent peptide <b>12f</b> [HisÂ(2-biphenyl)-Trp-HisÂ(2-biphenyl)]
displayed high in vitro activity against <i>C. neoformans</i> (IC<sub>50</sub> = 0.35 μg/mL, MIC = MFC = 0.63 μg/mL)
with a selectivity index of >28 and 2 times higher potency compared
to amphotericin B. Peptide <b>12f</b> exhibited proteolytic
stability, with no apparent hemolytic activity. The mechanism of action
study of <b>12f</b> by confocal laser scanning microscopy and
electron microscopy indicates nuclear fragmentation and membrane disruption
of <i>C. neoformans</i> cells. Combinations of <b>12f</b> with fluconazole and amphotericin B at subinhibitory concentration
were synergistic against <i>C. neoformans.</i> This study
suggests that <b>12f</b> is a new structural class of amphiphilic
peptide with rapid fungicidal activity caused by <i>C. neoformans</i>
Synthesis and Antimicrobial Evaluation of Fire Ant Venom Alkaloid Based 2‑Methyl-6-alkyl‑Δ<sup>1,6</sup>-piperideines
The first synthesis of 2-methyl-6-pentadecyl-Δ<sup>1,6</sup>-piperideine (<b>1</b>), a major alkaloid of the piperideine
chemotype in fire ant venoms, and its analogues, 2-methyl-6-tetradecyl-Δ<sup>1,6</sup>-piperideine (<b>2</b>) and 2-methyl-6-hexadecyl-Δ<sup>1,6</sup>-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 IC<sub>50</sub> values of 6.6 and
12.4 μg/mL, respectively, and antibacterial activity against
vancomycin-resistant <i>Enterococcus faecium</i> with an
IC<sub>50</sub> 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 IC<sub>50</sub> values in the range of 5.0–6.7 and 2.7–4.0
μg/mL, respectively
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)Âphenyl)Âpropan-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 (IC<sub>50</sub> 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
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 IC<sub>50</sub> 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
LC-MS- and <sup>1</sup>H 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 (<sup>1</sup>H 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)Âarabinofuranoside,
respectively. Compound <b>1</b> exhibited IC<sub>50</sub> 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 IC<sub>50</sub> values of 9.2 and 6.8 μg/mL, respectively. This study demonstrates
that utilization of the combined LC-MS and <sup>1</sup>H NMR analytical
tools is an improved chemical screening approach for hit prioritization
in natural product drug discovery
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
Bioactive Formylated Flavonoids from <i>Eugenia rigida</i>: Isolation, Synthesis, and X‑ray Crystallography
Two new flavonoids, <i>rac</i>-6-formyl-5,7-dihydroxyflavanone
(<b>1</b>) and 2′,6′-dihydroxy-4′-methoxy-3′-methylchalcone
(<b>2</b>), together with five known derivatives, <i>rac</i>-8-formyl-5,7-dihydroxyflavanone (<b>3</b>), 4′,6′-dihydroxy-2′-methoxy-3′-methyldihydrochalcone
(<b>4</b>), <i>rac</i>-7-hydroxy-5-methoxy-6-methylflavanone
(<b>5</b>), 3′-formyl-2′,4′,6′-trihydroxy-5′-methyldihydrochalcone
(<b>6</b>), and 3′-formyl-2′,4′,6′-trihydroxydihydrochalcone
(<b>7</b>), were isolated from the leaves of <i>Eugenia
rigida</i>. The individual (<i>S</i>)- and (<i>R</i>)-enantiomers of <b>1</b> and <b>3</b>, together
with the corresponding formylated flavones <b>8</b> (6-formyl-5,7-dihydroxyflavone)
and <b>9</b> (8-formyl-5,7-dihydroxyflavone), as well as 2′,4′,6′-trihydroxychalcone
(<b>10</b>), 3′-formyl-2′,4′,6′-trihydroxychalcone
(<b>11</b>), and the corresponding 3′-formyl-2′,4′,6′-trihydroxydihydrochalcone
(<b>7</b>) and 2′,4′,6′-trihydroxydihydrochalcone
(<b>12</b>), were synthesized. The structures of the isolated
and synthetic compounds were established via NMR, HRESIMS, and electronic
circular dichroism data. In addition, the structures of <b>3</b>, <b>5</b>, and <b>8</b> were confirmed by single-crystal
X-ray diffraction crystallography. The isolated and synthetic flavonoids
were evaluated for their antimicrobial and cytotoxic activities against
a panel of microorganisms and solid tumor cell lines
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 IC<sub>50</sub> 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 IC<sub>50</sub>/IC<sub>90</sub> values of 0.49/0.81 μg/mL compared to the positive control DFMO (IC<sub>50</sub>/IC<sub>90</sub>: 3.02/8.05 μg/mL). Furthermore, in antimalarial, antimicrobial, anti-inflammatory, PPAR and cytotoxic assays, some compounds have demonstrated moderate inhibitory potentials.</p