Epigenetic Tailoring for the Production of Anti-Infective Cytosporones from the Marine Fungus Leucostoma persoonii

Recent genomic studies have demonstrated that fungi can possess gene clusters encoding for the production of previously unobserved secondary metabolites. Activation of these attenuated or silenced genes to obtain either improved titers of known compounds or new ones altogether has been a subject of considerable interest. In our efforts to discover new chemotypes that are effective against infectious diseases, including malaria and methicillin-resistant Staphylococcus aureus (MRSA), we have isolated a strain of marine fungus, Leucostoma persoonii, that produces bioactive cytosporones. Epigenetic modifiers employed to activate secondary metabolite genes resulted in enhanced production of known cytosporones B (1, 360%), C (2, 580%) and E (3, 890%), as well as the production of the previously undescribed cytosporone R (4). Cytosporone E was the most bioactive, displaying an IC90 of 13 µM toward Plasmodium falciparum, with A549 cytotoxicity IC90 of 437 µM, representing a 90% inhibition therapeutic index (TI90 = IC90 A459/IC90 P. falciparum) of 33. In addition, cytosporone E was active against MRSA with a minimal inhibitory concentration (MIC) of 72 µM and inhibition of MRSA biofilm at roughly half that value (minimum biofilm eradication counts, MBEC90, was found to be 39 µM)

4(1H)-quinolones having antimalarial activity with reduced chemical resistance

Provided are 4(1H)-quinolone derivatives effective in inhibiting or eliminating the viability of at least one of the stages in the life-cycle of the malarial parasite, and to show a reduced propensity to induce resistance to the compound by the target parasite. In particular, the compounds can be derivatives of phenoxyethoxy-quinolones, and including, but not only, 7-(2-phenoxyethoxy)quinolin derivatives. These compounds may be administered by themselves, with at least one other derivative compound, or with other antimalarial compounds, to an animal or human subject. The therapeutic compositions can be and formulated to reduce the extent of a Plasmodium infection in the recipient subject, or to reduce the likelihood of the onset or establishment of a Plasmodium infection if administered prior to the parasite contacting the subject. The therapeutic compositions can be formulated to provide an effective single dose amount of an antimalarial compound or multiple doses for administering over a period of time

Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure–Activity and Structure–Property Relationship Studies

Malaria deaths have been decreasing over the last 10–15 years, with global mortality rates having fallen by 47% since 2000. While the World Health Organization (WHO) recommends the use of artemisinin-based combination therapies (ACTs) to combat malaria, the emergence of artemisinin resistant strains underscores the need to develop new antimalarial drugs. Recent in vivo efficacy improvements of the historical antimalarial ICI 56,780 have been reported, however, with the poor solubility and rapid development of resistance, this compound requires further optimization. A series of piperazine-containing 4(1H)-quinolones with greatly enhanced solubility were developed utilizing structure–activity relationship (SAR) and structure–property relationship (SPR) studies. Furthermore, promising compounds were chosen for an in vivo scouting assay to narrow selection for testing in an in vivo Thompson test. Finally, two piperazine-containing 4(1H)-quinolones were curative in the conventional Thompson test and also displayed in vivo activity against the liver stages of the parasite

Synthesis and Activity of a New Series of Antileishmanial Agents

We have determined that tetrahydroindazoles such as 1 show potent activity against Leishmania donovani, the causative agent of leishmaniasis. While the Hsp90 activity and anticancer properties of 1 have previously been explored, we present here our efforts to optimize their activity against L. donovani via the synthesis of novel analogues designed to probe the hydrophobic pocket of the protozoan Hsp90 orthologue, specifically through the auspices of functionalization of an amine embedded into the scaffold

Screening Mangrove Endophytic Fungi for Antimalarial Natural Products

We conducted a screening campaign to investigate fungi as a source for new antimalarial compounds. A subset of our fungal collection comprising Chinese mangrove endophytes provided over 5000 lipophilic extracts. We developed an accelerated discovery program based on small-scale cultivation for crude extract screening and a high-throughput malaria assay. Criteria for hits were developed and high priority hits were subjected to scale-up cultivation. Extracts from large scale cultivation were fractionated and these fractions subjected to both in vitro malaria and cytotoxicity screening. Criteria for advancing fractions to purification were developed, including the introduction of a selectivity index and by dereplication of known metabolites. From the Chinese mangrove endophytes, four new compounds (14–16, 18) were isolated including a new dimeric tetrahydroxanthone, dicerandrol D (14), which was found to display the most favorable bioactivity profile

Synthesis and Activity of a New Series of Antileishmanial Agents

We have determined that tetrahydroindazoles such as <b>1</b> show potent activity against <i>Leishmania donovani</i>, the causative agent of leishmaniasis. While the Hsp90 activity and anticancer properties of <b>1</b> have previously been explored, we present here our efforts to optimize their activity against <i>L. donovani</i> via the synthesis of novel analogues designed to probe the hydrophobic pocket of the protozoan Hsp90 orthologue, specifically through the auspices of functionalization of an amine embedded into the scaffold

ICI 56,780 Optimization: Structure–Activity Relationship Studies of 7‑(2-Phenoxyethoxy)-4(1<i>H</i>)‑quinolones with Antimalarial Activity

Though malaria mortality rates are down 48% globally since 2000, reported occurrences of resistance against current therapeutics threaten to reverse that progress. Recently, antimalarials that were once considered unsuitable therapeutic agents have been revisited to improve physicochemical properties and efficacy required for selection as a drug candidate. One such compound is 4­(1<i>H</i>)-quinolone ICI 56,780, which is known to be a causal prophylactic that also displays blood schizonticidal activity against <i>P. berghei.</i> Rapid induction of parasite resistance, however, stalled its further development. We have completed a full structure–activity relationship study on 4­(1<i>H</i>)-quinolones, focusing on the reduction of cross-resistance with atovaquone for activity against the clinical isolates W2 and TM90-C2B, as well as the improvement of microsomal stability. These studies revealed several frontrunner compounds with superb in vivo antimalarial activity. The best compounds were found to be curative with all mice surviving a <i>Plasmodium berghei</i> infection after 30 days

ICI 56,780 Optimization: Structure–Activity Relationship Studies of 7‑(2-Phenoxyethoxy)-4(1<i>H</i>)‑quinolones with Antimalarial Activity

Though malaria mortality rates are down 48% globally since 2000, reported occurrences of resistance against current therapeutics threaten to reverse that progress. Recently, antimalarials that were once considered unsuitable therapeutic agents have been revisited to improve physicochemical properties and efficacy required for selection as a drug candidate. One such compound is 4­(1<i>H</i>)-quinolone ICI 56,780, which is known to be a causal prophylactic that also displays blood schizonticidal activity against <i>P. berghei.</i> Rapid induction of parasite resistance, however, stalled its further development. We have completed a full structure–activity relationship study on 4­(1<i>H</i>)-quinolones, focusing on the reduction of cross-resistance with atovaquone for activity against the clinical isolates W2 and TM90-C2B, as well as the improvement of microsomal stability. These studies revealed several frontrunner compounds with superb in vivo antimalarial activity. The best compounds were found to be curative with all mice surviving a <i>Plasmodium berghei</i> infection after 30 days