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

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

Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1<i>H</i>)‑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(1<i>H</i>)-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(1<i>H</i>)-quinolones were curative in the conventional Thompson test and also displayed in vivo activity against the liver stages of the parasite

Bastimolide A, a Potent Antimalarial Polyhydroxy Macrolide from the Marine Cyanobacterium <i>Okeania hirsuta</i>

Bastimolide A (<b>1</b>), a polyhydroxy macrolide with a 40-membered ring, was isolated from a new genus of the tropical marine cyanobacterium <i>Okeania hirsuta</i>. This novel macrolide was defined by spectroscopy and chemical reactions to possess one 1,3-diol, one 1,3,5-triol, six 1,5-diols, and one <i>tert</i>-butyl group; however, the relationships of these moieties to one another were obscured by a highly degenerate ¹H NMR spectrum. Its complete structure and absolute configuration were therefore unambiguously determined by X-ray diffraction analysis of the nona-<i>p</i>-nitrobenzoate derivative (<b>1d</b>). Pure bastimolide A (<b>1</b>) showed potent antimalarial activity against four resistant strains of <i>Plasmodium falciparum</i> with IC₅₀ values between 80 and 270 nM, although with some toxicity to the control Vero cells (IC₅₀ = 2.1 μM), and thus represents a potentially promising lead for antimalarial drug discovery. Moreover, rigorous establishment of its molecular arrangement gives fresh insight into the structures and biosynthesis of cyanobacterial polyhydroxymacrolides