Publication
Discovery of novel antimalarials using the witkop-winterfeldt and indole chemistries
| Summary: | Despite excellent drug discovery programs and unprecedent commitment to eliminate malaria, this protozoan disease remains a major cause of mortality and morbidity worldwide, and specially in developing nations. Apart from socio-economic issues, drug-resistance seems to be the major causing factor for the malaria incidence in these countries. This project aimed to disclose new leads that are active against drug-resistant malaria parasites, acting as multi-stage antimalarials with new mechanisms of action (MoA). A common synthetic strategy was explored to prepare new chemical entities (NCE) and structurally related heterocycles, which included the synthesis of indoles, quinolones and spiroindolones. A library of pyrroloquinolones was prepared based on the Winterfeldt chemistry. The Winterfeldt precursors were usually prepared based on Pictet-Spengler reactions, followed by N-acylation or N-alkylation. A pyrroloquinolone lead was disclosed from this small library, with nanomolar antimalarial activity, against blood-stage and liver stage parasites. The lead compound revealed to be a DHODH and cytochrome bc1 inhibitor, targeting two components of the plasmodial mitochondrial electron transport chain, and favorable pharmacokinetic properties. The lead compound also revealed to be stable (absence of putative hydroxylated metabolites), after incubation with human and mouse liver microsomes. A secondary library of polyfunctionalized indoles was prepared via A3 coupling of aldehydes, amines and alkynes. The exploratory project that aimed for the diversity-oriented synthesis of novel pyrroloquinoles yielded a synthetic intermediate with low sub-micromolar antimalarial activity against drug-sensitive and drug-resistant blood stage malaria parasites with unknown MoA, which has an inhibitory activity comparable to the most potent indole antimalarials known. The lead compound from this library enabled systemic exposure after oral administration and limited aqueous kinetic solubility. A tertiary library of spiroindolones was also prepared, using previously prepared Winterfeldt precursors. The extension of this preliminary strategy of repurposing tetrahydro-ß-carbolines as synthetic intermediates for oxidative rearrangement yielded unprecedented antimalarial spiroindolones with nanomolar activity against drug-sensitive and drug-resistant blood-stage malaria parasites. This project was a contribution for the development of three small libraries of synthetically related N-containing heterocycles, with promising antimalarial activity. |
|---|---|
| Main Authors: | Silva, Gustavo Da |
| Subject: | Biblioteca combinatoria Compostos-lider antimalaricos Espiroindolonas Indoles Quimica de heterociclos Quinolonas Antimalarial leads Combinatory library Heterocyclic chemistry Quinolones Spiroindolones |
| Year: | 2022 |
| Country: | Portugal |
| Document type: | doctoral thesis |
| Access type: | restricted access |
| Associated institution: | Universidade de Lisboa |
| Language: | English |
| Origin: | Repositório da Universidade de Lisboa |
| Summary: | Despite excellent drug discovery programs and unprecedent commitment to eliminate malaria, this protozoan disease remains a major cause of mortality and morbidity worldwide, and specially in developing nations. Apart from socio-economic issues, drug-resistance seems to be the major causing factor for the malaria incidence in these countries. This project aimed to disclose new leads that are active against drug-resistant malaria parasites, acting as multi-stage antimalarials with new mechanisms of action (MoA). A common synthetic strategy was explored to prepare new chemical entities (NCE) and structurally related heterocycles, which included the synthesis of indoles, quinolones and spiroindolones. A library of pyrroloquinolones was prepared based on the Winterfeldt chemistry. The Winterfeldt precursors were usually prepared based on Pictet-Spengler reactions, followed by N-acylation or N-alkylation. A pyrroloquinolone lead was disclosed from this small library, with nanomolar antimalarial activity, against blood-stage and liver stage parasites. The lead compound revealed to be a DHODH and cytochrome bc1 inhibitor, targeting two components of the plasmodial mitochondrial electron transport chain, and favorable pharmacokinetic properties. The lead compound also revealed to be stable (absence of putative hydroxylated metabolites), after incubation with human and mouse liver microsomes. A secondary library of polyfunctionalized indoles was prepared via A3 coupling of aldehydes, amines and alkynes. The exploratory project that aimed for the diversity-oriented synthesis of novel pyrroloquinoles yielded a synthetic intermediate with low sub-micromolar antimalarial activity against drug-sensitive and drug-resistant blood stage malaria parasites with unknown MoA, which has an inhibitory activity comparable to the most potent indole antimalarials known. The lead compound from this library enabled systemic exposure after oral administration and limited aqueous kinetic solubility. A tertiary library of spiroindolones was also prepared, using previously prepared Winterfeldt precursors. The extension of this preliminary strategy of repurposing tetrahydro-ß-carbolines as synthetic intermediates for oxidative rearrangement yielded unprecedented antimalarial spiroindolones with nanomolar activity against drug-sensitive and drug-resistant blood-stage malaria parasites. This project was a contribution for the development of three small libraries of synthetically related N-containing heterocycles, with promising antimalarial activity. |
|---|