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Parallel Synthesis of Piperazine Tethered Thiazole Compounds with Antiplasmodial Activity.

ABSTRACT: Thiazole and piperazine are two important heterocyclic rings that play a prominent role in nature and have a broad range of applications in agricultural and medicinal chemistry. Herein, we report the parallel synthesis of a library of diverse piperazine-tethered thiazole compounds. The reaction of piperazine with newly generated 4-chloromethyl-2-amino thiazoles led to the desired piperazine thiazole compounds with high purities and good overall yields. Using a variety of commercially available carboxylic acids, the parallel synthesis of a variety of disubstituted 4-(piperazin-1-ylmethyl)thiazol-2-amine derivatives is described. the screening of the compounds led to the identification of antiplasmodial compounds that exhibited interesting antimalarial activity, primarily against the Plasmodium falciparum chloroquine-resistant Dd2 strain. The hit compound 2291-61 demonstrated an antiplasmodial EC₅₀ of 102 nM in the chloroquine-resistant Dd2 strain and a selectivity of over 140.

SUBMITTER: Rayala R

PROVIDER: S-EPMC10743568 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Parallel Synthesis of Piperazine Tethered Thiazole Compounds with Antiplasmodial Activity.

Rayala Ramanjaneyulu R Chaudhari Prakash P Bunnell Ashley A Roberts Bracken B Chakrabarti Debopam D Nefzi Adel A

International journal of molecular sciences 20231212 24

Thiazole and piperazine are two important heterocyclic rings that play a prominent role in nature and have a broad range of applications in agricultural and medicinal chemistry. Herein, we report the parallel synthesis of a library of diverse piperazine-tethered thiazole compounds. The reaction of piperazine with newly generated 4-chloromethyl-2-amino thiazoles led to the desired piperazine thiazole compounds with high purities and good overall yields. Using a variety of commercially available c ...[more]

PMID: 38139243

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Project description:Malaria, caused by Plasmodium parasites, continues to be a devastating global health issue. Despite a decline in malaria related deaths over the last decade, overall progress has plateaued. Key challenges to malaria prevention and control include the lack of a broadly effective vaccine and parasite drug resistance, including to the current gold standard artemisinin combination therapies (ACTs). New drugs with unique modes of action are therefore a priority for both the treatment and prevention of malaria. Unlike treatment drugs which need to kill parasites quickly to reduce or prevent clinical symptoms, compounds that kill parasites more slowly may be an option for malaria prevention. Natural products and natural product derived compounds have historically been an excellent source of antimalarial drugs, including the artemisinin component of ACTs. In this study, 424 natural product derived compounds were screened for in vitro activity against P. falciparum in assays designed to detect slow action activity, with 46 hit compounds identified as having >50% inhibition at 10 μM. Dose response assays revealed nine compounds with submicromolar activity, with slow action activity confirmed for two compounds, alstonine and himbeline (50% inhibitory concentration (IC50) 0.17 and 0.58 μM, respectively). Both compounds displayed >140-fold better activity against P. falciparum versus two human cell lines (Selectivity Index (SI) >1,111 and > 144, respectively). Importantly, P. falciparum multi-drug resistant lines showed no cross-resistance to alstonine or himbeline, with some resistant lines being more sensitive to these two compounds compared to the drug sensitive line. In addition, alstonine displayed cross-species activity against the zoonotic species, P. knowelsi (IC50 ~1 μM). Outcomes of this study provide a starting point for further investigations into these compounds as antiplasmodial drug candidates and the investigation of their molecular targets.

Dataset Information

Parallel Synthesis of Piperazine Tethered Thiazole Compounds with Antiplasmodial Activity.

Publications

Parallel Synthesis of Piperazine Tethered Thiazole Compounds with Antiplasmodial Activity.

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