Primaquine is a traditional antimalarial drug with low parasitic resistance and generally good acceptance at higher doses, which has been used for over 60 years in malaria treatment. However, several limitations related to its hematotoxicity have been reported. It is believed that this toxicity comes from the hydroxylation of the C-5 and C-6 positions of its 8-aminoquinoline ring before binding to the molecular target: the quinone reductase II (NQO2) human protein. In this study we propose primaquine derivatives, with substitution at position C-6 of the 8-aminoquinoline ring, planned to have better binding to NQO2, compared to primaquine, but with a reduced toxicity related to the C-5 position being possible to be oxidized. On this sense the proposed analogues were suggested in order to reduce or inhibit hydroxylation and further oxidation to hemotoxic metabolites. Five C-6 substituted primaquine analogues were selected by de novo design and further submitted to docking and molecular dynamics simulations. Our results suggest that all analogues bind better to NQO2 than primaquine and may become better antimalarials. However, the analogues 3 and 4 are predicted to have a better activity/toxicity balance.
- MeSH
- chinonreduktasy antagonisté a inhibitory chemie MeSH
- inhibitory enzymů chemie MeSH
- katalytická doména MeSH
- lidé MeSH
- primachin analogy a deriváty chemie MeSH
- sekundární struktura proteinů MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- termodynamika MeSH
- vazba proteinů MeSH
- vodíková vazba MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Diagnosis and therapy of cutaneous leishmaniasis (CL) can be difficult due to the variability of the clinical pictures and resistance to therapy. There is no vaccine currently available for CL. The aim of the present review is to describe different topical treatment modalities for old world CL. The mainstays of treatment for old world CL are pentavalent antimony compounds which are administered parenterally or intralesionally. New topical treatment alternatives have been available within the past few years. Amongst several treatments used topically, physical therapies including cryotherapy, heat therapy and CO2 laser are promising for the treatment of old world CL. Along with that, other randomized placebo controlled trials should be designed to find new effective therapeutic regimens.
- MeSH
- amfotericin B aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- antimon terapeutické užití MeSH
- aplikace kožní MeSH
- aplikace lokální MeSH
- fototerapie metody využití MeSH
- imidazoly aplikace a dávkování terapeutické užití MeSH
- indukovaná hypertermie metody využití MeSH
- kryoterapie metody využití MeSH
- laserová terapie metody využití MeSH
- leishmanióza kožní diagnóza etiologie terapie MeSH
- lidé MeSH
- naftochinony aplikace a dávkování terapeutické užití MeSH
- organokovové sloučeniny terapeutické užití MeSH
- paromomycin aplikace a dávkování terapeutické užití MeSH
- primachin analogy a deriváty aplikace a dávkování terapeutické užití MeSH
- rostlinné extrakty terapeutické užití MeSH
- terapie klasifikace metody využití MeSH
- toll-like receptor 7 aplikace a dávkování terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
