Albopunctatone, an Antiplasmodial Anthrone-Anthraquinone from the Australian Ascidian <i>Didemnum albopunctatum</i>

Chemical investigation of a MeOH extract of the Great Barrier Reef ascidian <i>Didemnum albopunctatum</i> has led to the isolation and identification of a new anthrone-anthraquinone, albopunctatone (<b>1</b>), together with the known 1,8-dihydroxy-9,10-anthraquinone (<b>2</b>). The structure of <b>1</b> was established from interpretation of 1D and 2D NMR spectroscopic and mass spectrometric data. The compounds were screened for antiplasmodial activity against chloroquine-resistant and -sensitive strains of the malaria parasite, <i>Plasmodium falciparum</i>. Albopunctatone (<b>1</b>) was moderately active against both strains (IC₅₀ 5.3 and 4.4 ± 0.5 μM, respectively), while <b>2</b> was inactive at doses up to 40 μM. Both compounds were also inactive up to 40 μM when tested against a variety of cancerous and normal human cell lines and the kinetoplastid <i>Trypanosoma brucei brucei</i>, indicating selectivity for the malaria parasite, <i>P. falciparum</i>

Tomentosones A and B, Hexacyclic Phloroglucinol Derivatives from the Thai Shrub <i>Rhodomyrtus tomentosa</i>

Two phloroglucinols named tomentosones A and B (<b>1</b> and <b>2</b>) that each possess a novel hexacyclic ring system were isolated from the CH₂Cl₂ extract of <i>Rhodomyrtus tomentosa</i> leaves. Their structures were elucidated from analyses of 2D NMR spectroscopic data. Tomentosone A inhibited the growth of chloroquine-resistant and -sensitive strains of the malaria parasite <i>Plasmodium falciparum</i>, with IC₅₀ values of 1.49 μM and 1.0 μM, respectively, while tomentosone B was significantly less active

Thiaplakortones A–D: Antimalarial Thiazine Alkaloids from the Australian Marine Sponge Plakortis lita

A high-throughput screening campaign using a prefractionated natural product library and an in vitro antimalarial assay identified active fractions derived from the Australian marine sponge Plakortis lita. Bioassay-guided fractionation of the CH₂Cl₂/CH₃OH extract from P. lita resulted in the purification of four novel thiazine-derived alkaloids, thiaplakortones A–D (<b>1</b>–<b>4</b>). The chemical structures of <b>1</b>–<b>4</b> were determined following analysis of 1D/2D NMR and MS data. Comparison of the chiro-optical data for <b>3</b> and <b>4</b> with literature values of related <i>N</i>-methyltryptophan natural products was used to determine the absolute configuration for both thiaplakortones C and D as 11<i>S</i>. Compounds <b>1</b>–<b>4</b> displayed significant growth inhibition against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum (IC₅₀ values <651 nM) and only moderate cytotoxicity against HEK293 cells (IC₅₀ values >3.9 μM). Thiaplakortone A (<b>1</b>) was the most active natural product, with IC₅₀ values of 51 and 6.6 nM against 3D7 and Dd2 lines, respectively

Antiplasmodial β‑Triketone–Flavanone Hybrids from the Flowers of the Australian Tree <i>Corymbia torelliana</i>

The methanol extract of the flowers of the Australian eucalypt tree <i>Corymbia torelliana</i> yielded six new β-triketone–flavanone hybrids, torellianones A–F (<b>1</b>–<b>6</b>), the tetrahydroxycyclohexane torellianol A (<b>7</b>), and known β-triketones (4<i>S</i>)-ficifolidione (<b>8</b>) and (4<i>R</i>)-ficifolidione (<b>9</b>), and β-triketone–flavanones kunzeanone A (<b>10</b>) and kunzeanone B (<b>11</b>). Torellianones A and B, C and D, and E and F were each isolated as inseparable diastereomeric mixtures. Exchange correlations observed in a ROESY spectrum indicated that <b>5</b> and <b>6</b> also interconverted between stable conformers. The structures of <b>1</b>–<b>7</b> were elucidated from the analysis of 1D/2D NMR and MS data. Relative configurations of torellianones C–F and torrellianol A were determined from analysis of ROESY data. Compounds <b>1</b>–<b>10</b> were tested for antiplasmodial activity against a drug-sensitive (3D7) strain of <i>Plasmodium falciparum</i>, with <b>3</b>–<b>6</b> and <b>8</b>–<b>10</b> showing limited antiplasmodial activity, with IC₅₀ values ranging from 3.2 to 16.6 μM

Pimentelamines A–C, Indole Alkaloids Isolated from the Leaves of the Australian Tree <i>Flindersia pimenteliana</i>

Three members of a new class of ascorbic acid-adduct indole alkaloids (<b>1</b>–<b>3</b>), a new prenylated indole alkaloid (<b>4</b>), and five known compounds (<b>5</b>–<b>9</b>) were isolated from the leaves of <i>Flindersia pimenteliana</i>. The structures of <b>1</b>–<b>4</b> were elucidated on the basis of their (+)-HRESIMS and 2D NMR spectroscopic data. Antiplasmodial activity was also reported for the natural products against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) <i>Plasmodium falciparum</i> with IC₅₀ values ranging from 0.19 to 3.6 μM

Novel Conjugated Quinoline–Indoles Compromise Plasmodium falciparum Mitochondrial Function and Show Promising Antimalarial Activity

A novel class of antimalarial compounds, based on an indol-3-yl linked to the 2-position of a 4-aminoquinoline moiety, shows promising activity against the malaria parasite, Plasmodium falciparum. Compounds with a quaternary nitrogen on the quinoline show improved activity against the chloroquine-resistant K1 strain. Nonquaternerized 4-aminoquinolines retain significant potency but are relatively less active against the K1 strain. Alkylation of the 4-amino group preferentially improves the activity against the chloroquine-sensitive 3D7 strain. The quinoline-indoles show only weak activity as inhibitors of β-hematin formation, and their activities are only weakly antagonized by a hemoglobinase inhibitor. The compounds appear to dissipate mitochondrial potential as an early event in their antimalarial action and therefore may exert their activity by compromising Plasmodium mitochondrial function. Interestingly, we observed a structural relationship between our compounds and the anticancer and anthelminthic compound, pyrvinium pamoate, which has also been proposed to exert its action via compromising mitochondrial function

Identification and In-Vitro ADME Assessment of a Series of Novel Anti-Malarial Agents Suitable for Hit-to-Lead Chemistry

Triage of a set of antimalaria hit compounds, identified through high throughput screening against the Chloroquine sensitive (3D7) and resistant (Dd2) parasite <i>Plasmodium falciparum</i> strains identified several novel chemotypes suitable for hit-to-lead chemistry investigation. The set was further refined through investigation of their <i>in vitro</i> ADME properties, which identified templates with good potential to be developed further as antimalarial agents. One example was profiled in an <i>in vivo</i> murine <i>Plasmodium berghei</i> model of malaria infection

Copper, Nickel, and Zinc Cyclam–Amino Acid and Cyclam–Peptide Complexes May Be Synthesized with “Click” Chemistry and Are Noncytotoxic

We describe the synthesis of cyclam metal complexes derivatized with amino acids or a tripeptide using a copper(I)-catalyzed Huisgen “click” reaction. The linker triazole formed during the synthesis plays an active coordinating role in the complexes. The reaction conditions do not racemize the amino acid stereocenters. However, a methylene group adjacent to the triazole is susceptible to H/D exchange under ambient conditions, an observation which has potentially important implications for structures involving stereocenters adjacent to triazoles in click-derived structures. The successful incorporation of several amino acids is described, including reactive tryptophan and cysteine side chains. All complexes are formed rapidly upon introduction of the relevant metal salt, including synthetically convenient cases where trifluoroacetate salts of cyclam derivatives are used directly in the metalation. None of the metal complexes displayed any cytotoxicity to mammalian cells, suggesting that the attachment of such complexes to amino acids and peptides does not induce toxicity, further supporting their potential suitability for labeling/imaging studies. One Cu­(II)–cyclam–triazole–cysteine disulfide complex displayed moderate activity against MCF-10A breast nontumorigenic epithelial cells

Polyoxygenated Cyclohexenes and Other Constituents of <i>Cleistochlamys kirkii</i> Leaves

Thirteen new metabolites, including the polyoxygenated cyclohexene derivatives cleistodiendiol (<b>1</b>), cleistodienol B (<b>3</b>), cleistenechlorohydrins A (<b>4</b>) and B (<b>5</b>), cleistenediols A–F (<b>6</b>–<b>11</b>), cleistenonal (<b>12</b>), and the butenolide cleistanolate (<b>13</b>), 2,5-dihydroxybenzyl benzoate (cleistophenolide, <b>14</b>), and eight known compounds (<b>2</b>, <b>15</b>–<b>21</b>) were isolated from a MeOH extract of the leaves of <i>Cleistochlamys kirkii</i>. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of compounds <b>1</b>, <b>17</b>, and <b>19</b> were established by single-crystal X-ray diffraction. The configuration of the exocyclic double bond of compound <b>2</b> was revised based on comparison of its NMR spectroscopic features and optical rotation to those of <b>1</b>, for which the configuration was determined by X-ray diffraction. Observation of the co-occurrence of cyclohexenoids and heptenolides in <i>C. kirkii</i> is of biogenetic and chemotaxonomic significance. Some of the isolated compounds showed activity against <i>Plasmodium falciparum</i> (3D7, Dd2), with IC₅₀ values of 0.2–40 μM, and against HEK293 mammalian cells (IC₅₀ 2.7–3.6 μM). While the crude extract was inactive at 100 μg/mL against the MDA-MB-231 triple-negative breast cancer cell line, some of its isolated constituents demonstrated cytotoxic activity with IC₅₀ values ranging from 0.03–8.2 μM. Compound <b>1</b> showed the most potent antiplasmodial (IC₅₀ 0.2 μM) and cytotoxic (IC₅₀ 0.03 μM, MDA-MB-231 cell line) activities. None of the compounds investigated exhibited translational inhibitory activity in vitro at 20 μM

Polyoxygenated Cyclohexenes and Other Constituents of <i>Cleistochlamys kirkii</i> Leaves

Thirteen new metabolites, including the polyoxygenated cyclohexene derivatives cleistodiendiol (<b>1</b>), cleistodienol B (<b>3</b>), cleistenechlorohydrins A (<b>4</b>) and B (<b>5</b>), cleistenediols A–F (<b>6</b>–<b>11</b>), cleistenonal (<b>12</b>), and the butenolide cleistanolate (<b>13</b>), 2,5-dihydroxybenzyl benzoate (cleistophenolide, <b>14</b>), and eight known compounds (<b>2</b>, <b>15</b>–<b>21</b>) were isolated from a MeOH extract of the leaves of <i>Cleistochlamys kirkii</i>. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of compounds <b>1</b>, <b>17</b>, and <b>19</b> were established by single-crystal X-ray diffraction. The configuration of the exocyclic double bond of compound <b>2</b> was revised based on comparison of its NMR spectroscopic features and optical rotation to those of <b>1</b>, for which the configuration was determined by X-ray diffraction. Observation of the co-occurrence of cyclohexenoids and heptenolides in <i>C. kirkii</i> is of biogenetic and chemotaxonomic significance. Some of the isolated compounds showed activity against <i>Plasmodium falciparum</i> (3D7, Dd2), with IC₅₀ values of 0.2–40 μM, and against HEK293 mammalian cells (IC₅₀ 2.7–3.6 μM). While the crude extract was inactive at 100 μg/mL against the MDA-MB-231 triple-negative breast cancer cell line, some of its isolated constituents demonstrated cytotoxic activity with IC₅₀ values ranging from 0.03–8.2 μM. Compound <b>1</b> showed the most potent antiplasmodial (IC₅₀ 0.2 μM) and cytotoxic (IC₅₀ 0.03 μM, MDA-MB-231 cell line) activities. None of the compounds investigated exhibited translational inhibitory activity in vitro at 20 μM