In Vitro and In Vivo Pharmacokinetics of Aminoalkylated Diarylpropanes NP085 and NP102

Abstract

cMalaria remains a great burden on humanity. Although significant advances have been made in the prevention and treatment of malaria, malaria control is now hindered by an increasing tolerance of the parasite to one or more drugs within artemisinin combination therapies; therefore, an urgent need exists for development of novel and improved therapies. The University of the Free State Chemistry Department previously synthesized an antimalarial compound, NP046. In vitro studies illustrated an enhanced efficacy against Plasmodium falciparum. However, NP046 showed low bioavailability. Efforts to enhance the bioavailability of NP046 have resulted in the synthesis of a number of aminoalkylated diarylpropanes, including NP085 and NP102. Pharmacokinetic studies were conducted in C57BL/6 mice, with 15 mg/kg NP085 or NP102 administered orally and the 5 mg/kg NP085 or NP102 administered intravenously. Blood samples were collected by means of tail bleeding at predetermined time intervals. Drug concentrations were determined using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and subsequently pharmacokinetic modeling was done for both compounds. NP085 and NP102 were incubated in vitro with human and mouse liver microsomes. Both compounds were also subjected to a parallel artificial membrane permeation assay. In vitro studies of NP085 and NP102 illustrated that both of the compounds are rapidly absorbed and undergo rapid hepatic metabolism. The maximum concentration of drug (C max ) obtained following oral administration of NP085 and NP102 was 0.2 ؎ 0.4 and 0.7 ؎ 0.3 M, respectively; the elimination half-life of both compounds was 6.1 h. NP085 and NP102 showed bioavailability levels of 8% and 22%, respectively.

Toward New Transmission-Blocking Combination Therapies: Pharmacokinetics of 10-Amino-Artemisinins and 11-Aza-Artemisinin and Comparison with Dihydroartemisinin and Artemether

“…From these values, the PK parameters clearance (CL), volume of distribution ( V ), and oral bioavailability ( F ) could be determined using the noncompartmental analysis software PK Solutions version 2.0, Summit Research Services, Montrose, USA. The area under the plasma concentration curve up to the last time point AUC 0–last was calculated by using the trapezoidal rule ( 90 ).…”

Solvent‐Controlled Hydrogenation of 2’‐Hydroxychalcones: A Simple Solution to the Total Synthesis of Bussealins

“…These compounds are precursors in the flavonoid biosynthesis and have been isolated from diverse plant species from around the globe. [1] 1,3-Diarylpropanes exhibit diverse biological activities, i. e. antifungal, [2] anti-inflammatory, [3] anticancer, [4] antiadipogenic, [5] antitubercular, [6] antimalarial, [7] and anti-Alzheimer, [8] to name a few. Owing to their wide range of bioactivities, 1,3-diarylpropanes have become of great interest to many research groups in chemistry, biomedicine as well as those in agricultural and food chemistry.…”

Substrate‐Controlled Hydrogenation of Flavanones: Selective Synthesis of 2′‐Hydroxy‐1,3‐Diarylpropanes and Flavans

“…[19] Taking into account these previous results, we then hydrogenated 4'-methylflavanone 1 b over a mixture of Pd/C 10 % catalyst (10 mol %) and Pd(OH) 2 20 % (10 mol %) (Catalyst B) in ethanol, obtaining 1,3-diarylpropane 3 b in excellent yield (Table 1, entry 5). Under these conditions, hydrogenation flavanones 1 a and 1 c afforded almost quantitatively 1,3-diarylpropanes 3 b and 3 c respectively (Table 1, entries 4,6).…”

“…1,3‐Diarylpropanes are a subclass of flavonoids which are precursors for flavonoid biosynthesis in plants and exhibit significant cytotoxic activity in several cancer cell lines [1] . In addition, 1,3‐diarylpropanes have shown antifungal, [2] anti‐inflammatory, [3] antiadipogenic, [4] antitubercular, [5] antimalarial, [6] anti‐Alzheimer [7] and antioxidant activities, [8] to name a few. 1,3‐Diarylpropanes have also shown strong inhibition of tyrosinase and exhibited strong skin‐whitening effects; therefore, these natural compounds are of growing industrial interest for the development of depigmenting agents [9] …”