Quinolone-based compounds, formulations, and uses thereof

Provided herein are quinolone-based compounds that can be used for treatment and/or prevention of malaria and formulations thereof. Also provided herein are methods of treating and/or preventing malaria in a subject by administering a quinolone-based compound or formulation thereof provided herein

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

Aminoalkoxycarbonyloxymethyl Ether Prodrugs with a pH-Triggered Release Mechanism: A Case Study Improving the Solubility, Bioavailability, and Efficacy of Antimalarial 4(1

Preclinical and clinical development of numerous small molecules is prevented by their poor aqueous solubility, limited absorption, and oral bioavailability. Herein, we disclose a general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues that display significantly improved aqueous solubility and enhanced oral bioavailability, restoring key requirements typical for drug candidate profiles. The prodrug is completely independent of biotransformations and animal-independent because it becomes an active compound via a pH-triggered intramolecular cyclization-elimination reaction. As a proof-of-concept, the utility of this novel amino AOCOM ether prodrug approach was demonstrated on an antimalarial compound series representing a variety of antimalarial 4(

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