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 His­(2-Ar)-Trp-His­(2-Ar) exhibit potent antifungal activity against <i>Cryptococcus neoformans</i> with high selectivity. The most potent peptide <b>12f</b> [His­(2-biphenyl)-Trp-His­(2-biphenyl)] displayed high in vitro activity against <i>C. neoformans</i> (IC₅₀ = 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^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

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

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

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

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 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