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

Hydroxylated Derivatives of NPC1161: Theoretical Insights into Their Potential Toxicity and the Feasibility and Regioselectivity of Their Formation

For antimalarial 8-aminoquinoline (8-AQ) drugs, the ionization potential (energy required to remove an electron) of their putative metabolites has been proposed to be correlated in part to their hemotoxicity potential. NPC1161 is a developmental candidate as an 8-AQ antimalarial drug. In this work, the ionization potentials (IPs) of the <i>S</i>-NPC1161 (NPC1161a) hydroxylated derivatives, which are possible metabolites derived from action of endogenous cytochrome P450 (CYP450) enzymes, were calculated at the B3LYP-SCRF­(PCM)/6-311++G**//B3LYP/6-31G** level in water. The derivative hydroxylated at N1′ (8-amino) was found to have the smallest IP of ∼430 kJ/mol, predicting that it would be the most hemotoxic. The calculated IPs of the derivatives hydroxylated at the C2 and C7 positions were ∼475 and ∼478 kJ/mol, respectively, whereas the calculated IPs of those hydroxylated at all other possible positions were between 480 and 490 kJ/mol. The homolytic bond dissociation energies (HBDEs) of all C–H/N–H bonds in NPC1161a were also calculated. The smaller HBDEs of the C–H/N–H bonds on the 8-amino side chain suggest that these positions are more easily hydroxylated compared to other sites. Molecular orbital analysis implies that the N1′ position should be the most reactive center when NPC1161 approaches the heme in CYP450

Antiprotozoal and Antimicrobial Compounds from the Plant Pathogen <i>Septoria pistaciarum</i>

Four new 1,4-dihydroxy-5-phenyl-2-pyridinone alkaloids, 17-hydroxy-<i>N</i>-(<i>O</i>-methyl)­septoriamycin A (<b>1</b>), 17-acetoxy-<i>N</i>-(<i>O</i>-methyl)­septoriamycin A (<b>2</b>), 13-(<i>S</i>)-hydroxy-<i>N</i>-(<i>O</i>-methyl)­septoriamycin A (<b>3</b>), and 13-(<i>R</i>)-hydroxy-<i>N</i>-(<i>O</i>-methyl)­septoriamycin A (<b>4</b>), together with the known compounds (+)-cercosporin (<b>5</b>), (+)-14-<i>O</i>-acetylcercosporin (<b>6</b>), (+)-di-<i>O</i>-acetylcercosporin (<b>7</b>), lumichrome, and brassicasterol, were isolated from an ethyl acetate extract of a culture medium of <i>Septoria pistaciarum</i>. Methylation of septoriamycin A (<b>8</b>) with diazomethane yielded three di-<i>O</i>-methyl analogues, two of which existed as mixtures of rotamers. We previously reported antimalarial activity of septoriamycin A. This compound also exhibited significant activity against <i>Leishmania donovani</i> promastigotes. Compounds <b>5</b>–<b>7</b> showed moderate in vitro activity against <i>L. donovani</i> promastigotes and chloroquine-sensitive (D6) and -resistant (W2) strains of <i>Plasmodium falciparum</i>, whereas compound <b>5</b> was fairly active against methicillin-sensitive and methicillin-resistant strains of <i>Staphylococcus aureus</i>. Compounds <b>5</b>–<b>7</b> also displayed moderate phytotoxic activity against both a dicot (lettuce, <i>Lactuca sativa</i>) and a monocot (bentgrass, <i>Agrostis stolonifera</i>) and cytotoxicity against a panel of cell lines

Isolation of Acacetin from <i>Calea urticifolia</i> with Inhibitory Properties against Human Monoamine Oxidase‑A and -B

<i>Calea urticifolia</i> (Asteraceae: Asteroideae) has long been used as a traditional medicine in El Salvador to treat arthritis and fever, among other illnesses. The chloroform extract of the leaves of <i>C. urticifolia</i> showed potent inhibition of recombinant human monoamine oxidases (MAO-A and -B). Further bioassay-guided fractionation led to the isolation of a flavonoid, acacetin, as the most prominent MAO inhibitory constituent, with IC₅₀ values of 121 and 49 nM for MAO-A and -B, respectively. The potency of MAO inhibition by acacetin was >5-fold higher for MAO-A (0.121 μM vs 0.640 μM) and >22-fold higher for MAO-B (0.049 μM vs 1.12 μM) as compared to apigenin, the closest flavone structural analogue. Interaction and binding characteristics of acacetin with MAO-A and -B were determined by enzyme-kinetic assays, enzyme–inhibitor complex binding, equilibrium–dialysis dissociation analyses, and computation analysis. Follow-up studies showed reversible binding of acacetin with human MAO-A and -B, resulting in competitive inhibition. Acacetin showed more preference toward MAO-B than to MAO-A, suggesting its potential for eliciting selective pharmacological effects that might be useful in the treatment of neurological and psychiatric disorders. In addition, the binding modes of acacetin at the enzymatic site of MAO-A and -B were predicted through molecular modeling algorithms, illustrating the high importance of ligand interaction with negative and positive free energy regions of the enzyme active site

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