Synthesis and Biological Evaluation of Epidithio‑, Epitetrathio‑, and bis-(Methylthio)diketopiperazines: Synthetic Methodology, Enantioselective Total Synthesis of Epicoccin G, 8,8′-<i>epi</i>-<i>ent</i>-Rostratin B, Gliotoxin, Gliotoxin G, Emethallicin E, and Haematocin and Discovery of New Antiviral and Antimalarial Agents

An improved sulfenylation method for the preparation of epidithio-, epitetrathio-, and bis-(methylthio)­diketopiperazines from diketopiperazines has been developed. Employing NaHMDS and related bases and elemental sulfur or bis­[bis­(trimethylsilyl)­amino]­trisulfide (<b>23</b>) in THF, the developed method was applied to the synthesis of a series of natural and designed molecules, including epicoccin G (<b>1</b>), 8,8′-<i>epi</i>-<i>ent</i>-rostratin B (<b>2</b>), gliotoxin (<b>3</b>), gliotoxin G (<b>4</b>), emethallicin E (<b>5</b>), and haematocin (<b>6</b>). Biological screening of selected synthesized compounds led to the discovery of a number of nanomolar antipoliovirus agents (i.e., <b>46</b>, 2,2′-<i>epi</i>-<b>46</b>, and <b>61</b>) and several low-micromolar anti-Plasmodium falciparum lead compounds (i.e., <b>46</b>, 2,2′-<i>epi</i>-<b>46</b>, <b>58</b>, <b>61</b>, and <b>1</b>)

Synthesis and Biological Evaluation of Epidithio‑, Epitetrathio‑, and bis-(Methylthio)diketopiperazines: Synthetic Methodology, Enantioselective Total Synthesis of Epicoccin G, 8,8′-<i>epi</i>-<i>ent</i>-Rostratin B, Gliotoxin, Gliotoxin G, Emethallicin E, and Haematocin and Discovery of New Antiviral and Antimalarial Agents

An improved sulfenylation method for the preparation of epidithio-, epitetrathio-, and bis-(methylthio)­diketopiperazines from diketopiperazines has been developed. Employing NaHMDS and related bases and elemental sulfur or bis­[bis­(trimethylsilyl)­amino]­trisulfide (<b>23</b>) in THF, the developed method was applied to the synthesis of a series of natural and designed molecules, including epicoccin G (<b>1</b>), 8,8′-<i>epi</i>-<i>ent</i>-rostratin B (<b>2</b>), gliotoxin (<b>3</b>), gliotoxin G (<b>4</b>), emethallicin E (<b>5</b>), and haematocin (<b>6</b>). Biological screening of selected synthesized compounds led to the discovery of a number of nanomolar antipoliovirus agents (i.e., <b>46</b>, 2,2′-<i>epi</i>-<b>46</b>, and <b>61</b>) and several low-micromolar anti-Plasmodium falciparum lead compounds (i.e., <b>46</b>, 2,2′-<i>epi</i>-<b>46</b>, <b>58</b>, <b>61</b>, and <b>1</b>)

Synthesis and Biological Evaluation of Epidithio‑, Epitetrathio‑, and bis-(Methylthio)diketopiperazines: Synthetic Methodology, Enantioselective Total Synthesis of Epicoccin G, 8,8′-<i>epi</i>-<i>ent</i>-Rostratin B, Gliotoxin, Gliotoxin G, Emethallicin E, and Haematocin and Discovery of New Antiviral and Antimalarial Agents

An improved sulfenylation method for the preparation of epidithio-, epitetrathio-, and bis-(methylthio)­diketopiperazines from diketopiperazines has been developed. Employing NaHMDS and related bases and elemental sulfur or bis­[bis­(trimethylsilyl)­amino]­trisulfide (<b>23</b>) in THF, the developed method was applied to the synthesis of a series of natural and designed molecules, including epicoccin G (<b>1</b>), 8,8′-<i>epi</i>-<i>ent</i>-rostratin B (<b>2</b>), gliotoxin (<b>3</b>), gliotoxin G (<b>4</b>), emethallicin E (<b>5</b>), and haematocin (<b>6</b>). Biological screening of selected synthesized compounds led to the discovery of a number of nanomolar antipoliovirus agents (i.e., <b>46</b>, 2,2′-<i>epi</i>-<b>46</b>, and <b>61</b>) and several low-micromolar anti-Plasmodium falciparum lead compounds (i.e., <b>46</b>, 2,2′-<i>epi</i>-<b>46</b>, <b>58</b>, <b>61</b>, and <b>1</b>)

Synthesis and Biological Evaluation of Epidithio‑, Epitetrathio‑, and bis-(Methylthio)diketopiperazines: Synthetic Methodology, Enantioselective Total Synthesis of Epicoccin G, 8,8′-<i>epi</i>-<i>ent</i>-Rostratin B, Gliotoxin, Gliotoxin G, Emethallicin E, and Haematocin and Discovery of New Antiviral and Antimalarial Agents

An improved sulfenylation method for the preparation of epidithio-, epitetrathio-, and bis-(methylthio)­diketopiperazines from diketopiperazines has been developed. Employing NaHMDS and related bases and elemental sulfur or bis­[bis­(trimethylsilyl)­amino]­trisulfide (<b>23</b>) in THF, the developed method was applied to the synthesis of a series of natural and designed molecules, including epicoccin G (<b>1</b>), 8,8′-<i>epi</i>-<i>ent</i>-rostratin B (<b>2</b>), gliotoxin (<b>3</b>), gliotoxin G (<b>4</b>), emethallicin E (<b>5</b>), and haematocin (<b>6</b>). Biological screening of selected synthesized compounds led to the discovery of a number of nanomolar antipoliovirus agents (i.e., <b>46</b>, 2,2′-<i>epi</i>-<b>46</b>, and <b>61</b>) and several low-micromolar anti-Plasmodium falciparum lead compounds (i.e., <b>46</b>, 2,2′-<i>epi</i>-<b>46</b>, <b>58</b>, <b>61</b>, and <b>1</b>)

Synthesis and Biological Evaluation of Epidithio‑, Epitetrathio‑, and bis-(Methylthio)diketopiperazines: Synthetic Methodology, Enantioselective Total Synthesis of Epicoccin G, 8,8′-<i>epi</i>-<i>ent</i>-Rostratin B, Gliotoxin, Gliotoxin G, Emethallicin E, and Haematocin and Discovery of New Antiviral and Antimalarial Agents

An improved sulfenylation method for the preparation of epidithio-, epitetrathio-, and bis-(methylthio)­diketopiperazines from diketopiperazines has been developed. Employing NaHMDS and related bases and elemental sulfur or bis­[bis­(trimethylsilyl)­amino]­trisulfide (<b>23</b>) in THF, the developed method was applied to the synthesis of a series of natural and designed molecules, including epicoccin G (<b>1</b>), 8,8′-<i>epi</i>-<i>ent</i>-rostratin B (<b>2</b>), gliotoxin (<b>3</b>), gliotoxin G (<b>4</b>), emethallicin E (<b>5</b>), and haematocin (<b>6</b>). Biological screening of selected synthesized compounds led to the discovery of a number of nanomolar antipoliovirus agents (i.e., <b>46</b>, 2,2′-<i>epi</i>-<b>46</b>, and <b>61</b>) and several low-micromolar anti-Plasmodium falciparum lead compounds (i.e., <b>46</b>, 2,2′-<i>epi</i>-<b>46</b>, <b>58</b>, <b>61</b>, and <b>1</b>)

A Chemical Genomic Analysis of Decoquinate, a <i>Plasmodium falciparum</i> Cytochrome <i>b</i> Inhibitor

Decoquinate has single-digit nanomolar activity against <i>in vitro</i> blood stage <i>Plasmodium falciparum</i> parasites, the causative agent of human malaria. <i>In vitro</i> evolution of decoquinate-resistant parasites and subsequent comparative genomic analysis to the drug-sensitive parental strain revealed resistance was conferred by two nonsynonymous single nucleotide polymorphisms in the gene encoding cytochrome <i>b</i>. The resultant amino acid mutations, A122T and Y126C, reside within helix C in the ubiquinol-binding pocket of cytochrome <i>b</i>, an essential subunit of the cytochrome <i>bc</i>₁ complex. As with other cytochrome <i>bc</i>₁ inhibitors, such as atovaquone, decoquinate has low nanomolar activity against <i>in vitro</i> liver stage <i>P. yoelii</i> and provides partial prophylaxis protection when administered to infected mice at 50 mg kg^–1. In addition, transgenic parasites expressing yeast dihydroorotate dehydrogenase are >200-fold less sensitive to decoquinate, which provides additional evidence that this drug inhibits the parasite’s mitochondrial electron transport chain. Importantly, decoquinate exhibits limited cross-resistance to a panel of atovaquone-resistant parasites evolved to harbor various mutations in cytochrome <i>b</i>. The basis for this difference was revealed by molecular docking studies, in which both of these inhibitors were shown to have distinctly different modes of binding within the ubiquinol-binding site of cytochrome <i>b</i>