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Old drugs in new therapeutic indications - the case of chloroquine

Grzybowski Bartosz A., Grynkiewicz Grzegorz

Polish Technical Review

2020

No. 1

5--10

Drug reposition is a viable strategy of pharmaceutical R & D, considerably reducing risk, cost and time needed for drug registration and implementation. Chloroquine, designed already in 1930 as a synthetic replacement for scarcely available alkaloid quinine, a traditional malaria treatment, was recently proposed as an antiviral substance, with putative efficacy in some cases of SARS COVID infections. This unexpected connection has revived interest in drug repositioning at large and in particular in the context of identifying antiviral preparations, critically needed in time of COVID-19 pandemia. The paper recounts the story of development of synthetic antmalarials and describes modern chemoinformatics tools, which can efficiently assist synthetic chemists in planning and executing both: drug repositioning and API manufacturing.

Zastosowanie znanych leków w nowych wskazaniach terapeutycznych (repozycjonowanie leków) jest obecnie akceptowane jako skrócona ścieżka do rejestracji i autoryzacji rynkowej nowego specyfiku. Przykładem takiej drogi znanej substancji do leku o nowym zastosowaniu jest historia chlorochiny, zaprojektowanej w latach 30-tych ubiegłego wieku w charakterze zastępstwa trudnodostępnej substancji pochodzenia naturalnego - chininy, skutecznej w leczeniu malarii. Według dostępnych danych chlorochina może się okazać przez długi czas pandemii jedynym specyfikiem o działaniu terapeutycznym w infekcjach wirusowych SARS COVID. W artykule przedstawiono rolę nowoczesnych narzędzi chemoinformatycznych, takich jak Chematica, we wspomaganiu zarówno procesu repozycjonowania leków, jak i syntezy chemicznej substancji o zastosowaniach farmaceutycznych i medycznych.

Development and validation of a sensitive and selective LC—MS/MS method for the determination of an antimalarial drug candidate in rat plasma, and its application to a preclinical pharmacokinetic study

Pires C., Kaiser M., Grünspan L. D., Barreto F., Innocente A., Gnoatto S., Laureano J. V., Araujo B., Costa T., Tasso L.

Acta Chromatographica

2016

Vol. 28, no. 4

439--453

An accurate and reliable LC—MS/MS assay was firstly developed and validated for quantitative determination of a new antimalarial prototype drug, 3β-hydroxyurs-12-en-28-oic acid (LAFIS 01), in rat plasma. Dexamethasone was employed as internal standard. Simple protein precipitation by acetonitrile for the sample preparation was used. Effective separation was achieved with Phenomenex Luna C18 (50 × 2 mm, 5 μm) column. The mobile phase consisted of (A) water and (B) acetonitrile, both containing 0.1% acetic acid, delivered by gradient elution. The column temperature was maintained at 40 °C. The LAFIS 01 was monitored by electrospray ionization interface, operating in the negative mode (ESI−) in multiple reactions monitoring (MRM), checking the transitions 455 > 455 for LAFIS 01 and 451 > 361 for the IS. Once LAFIS 01 demonstrated low fragmentation by collision-induced dissociation (CID) nonpresenting abundant high-intensity fragments to meet the desired concentration levels quantification, only pseudomolecular ion was monitored. The flow rate was 500 μL min−1. The lower limit of quantitation achieved was 10 ng mL−1 and linearity was observed from 10 to 500 ng mL−1. The relative standard deviation (RSD) values of the intra- and inter-assay precisions of the method were below 8.42 and 7.94%, respectively. The accuracy ranged from 92.05 to 102.94%. The extraction recovery of LAFIS 01 and IS was up to 90%. The method showed linearity, precision, accuracy, sensitivity, and stability required to quantify LAFIS 01 in preclinical pharmacokinetic study.