RESUMO
In the search of novel chemotherapeutic agents for emerging drug resistant parasites, the hybridization approaches have successfully emerged as an efficient tool in malarial chemotherapy. Herein, a rational design and synthesis of novel 8-aminoquinoline and pyrazolopyrimidine hybrids and their antimalarial activity against wild type Plasmodium falciparum (Pf_NF54) and resistant strain (Pf_K1) is reported. The medicinal chemistry approach to expand the scope of this series resulted in an identification of potent compounds with nanomolar potency (best IC50 5-10nM). Systematic structure activity relationship (SAR) studies revealed that pyrazolopyrimidine and 8-aminoquinoline ring are essential for achieving good P. falciparum potency. The docking study revealed that the compound 6 can retain some of the critical interactions within pfDHODH drug target.
Assuntos
Aminoquinolinas/química , Aminoquinolinas/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Humanos , Malária Falciparum/tratamento farmacológico , Simulação de Acoplamento Molecular , Testes de Sensibilidade Parasitária , Pirazóis/química , Pirazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
Aminopyrazinamides originated from a high throughput screen targeting the Mycobacterium smegmatis (Msm) GyrB ATPase. This series displays chemical tractability, robust structure-activity relationship, and potent antitubercular activity. The crystal structure of Msm GyrB in complex with one of the aminopyrazinamides revealed promising attributes of specificity against other broad spectrum pathogens and selectivity against eukaryotic kinases due to novel interactions at hydrophobic pocket, unlike other known GyrB inhibitors. The aminopyrazinamides display excellent mycobacterial kill under in vitro, intracellular, and hypoxic conditions.