New derivatives of the multi-stage active Malaria Box compound MMV030666 and their antiplasmodial potencies

MMV's Malaria Box compound MMV030666 shows multi-stage activity against various strains of Plasmodium falciparum and lacks resistance development. To evaluate the importance of its diarylether partial structure, diarylthioethers and diphenylamines with varying substitution patterns were prepared. A number of evident structure-activity relationships were revealed. Physicochemical and pharmacokinetic parameters were determined experimentally (passive permeability) or calculated. Compared to the lead compound a diarylthioether was more active and less cytotoxic resulting in an excellent selectivity index of 850. In addition, pharmacokinetic and physicochemical parameters were improved

Synthesis and structure-activity relationships of new 2-phenoxybenzamides with antiplasmodial activity

The 2-phenoxybenzamide 1 from theMedicines for Malaria Venture Malaria Box Project has shown promising multi-stage activity against different strains of P. falciparum. It was successfully synthesized via a retrosynthetic approach. Subsequently, twenty-one new derivatives were prepared and tested for their in vitro activity against blood stages of the NF54 strain of P. falciparum. Several insights into structure-activity relationships were revealed. The antiplasmodial activity and cytotoxicity of compounds strongly depended on the substitution pattern of the anilino partial structure as well as on the size of substituents. The diaryl ether partial structure had further impacts on the activity. Additionally, several physicochemical and pharmacokinetic parameters were calculated (log P, log D7.4 and ligand efficiency) or determined experimentally (passive permeability and CYP3A4 inhibition). The tertbutyl- 4-{4-[2-(4-fluorophenoxy)-3-(trifluoromethyl)benzamido]phenyl}piperazine-1-carboxylate possesses high antiplasmodial activity against P. falciparum NF54 (PfNF54 IC50 = 0.2690 M) and very low cytotoxicity (L-6 cells IC50 = 124.0 M) resulting in an excellent selectivity index of 460. Compared to the lead structure 1 the antiplasmodial activity was improved as well as the physicochemical and some pharmacokinetic parameters

Antiproliferative Carvotacetones from <i>Sphaeranthus africanus</i>

Five carvotacetone derivatives, including two known ones, 3,5-diangeloyloxy-7-hydroxycarvotacetone (<b>1</b>) and 3-angeloyl­oxy-5-[2″,3″-epoxy-2″-methylbutanoyloxy]-7-hydroxycarvotacetone (<b>2</b>), along with three new compounds, 3-angeloyloxy-5-[3″-chloro-2″-hydroxy-2″-methylbutanoyloxy]-7-hydroxycarvotacetone (<b>3</b>), 5-angeloyloxy-7-hydroxy-3-tigloyloxycarvotacetone (<b>4</b>), and 3-angeloyl­oxy-5,7-dihydroxycarvotacetone (<b>5</b>), were isolated from the aerial parts of <i>Sphaeranthus africanus</i> collected in Vietnam. Bioassay-guided fractionation was monitored by the antiproliferative activity on CCRF-CEM human cancer cells. The structures of compounds <b>1</b>–<b>5</b> were determined on the basis of NMR spectroscopic and mass spectrometric data. Activities of compounds <b>1</b>–<b>5</b> were evaluated in vitro against the human cancer cell lines CCRF-CEM, MDA-MB-231, U-251, and HCT-116. All compounds exhibited significant antiproliferative activity against all four cancer cell lines. CCRF-CEM was most sensitive to the compounds, with IC₅₀ values ranging from 0.6 to 1.5 μM. Compounds <b>3</b> and <b>4</b> possessed the highest activity, with IC₅₀ values in the four cell lines ranging from 0.6 to 2.9 μM and 1.3 to 2.5 μM, respectively. These compounds also showed inhibitory activity toward the HEK-293 human embryonic kidney cells with IC₅₀ values ranging from 2.5 to 5.5 μM. This is the first time that antiproliferative activity of <i>S. africanus</i> has been reported, and <b>1</b>–<b>5</b> are the most cytotoxic carvotacetone derivatives reported so far

Phylogenomic analyses of the Photinia complex support the recognition of a new genus Phippsiomeles and the resurrection of a redefined Stranvaesia in Maleae (Rosaceae)

Photinia and its morphologically similar allies in Maleae (Rosaceae) consist of five currently recognized genera: Aronia, Heteromeles, Photinia, Pourthiaea, and Stranvaesia, and 68 species, distributed in Asia and North and Central America. Despite previous efforts to clarify relationships in this group, the generic delimitations have remained uncertain. Our goals were to reconstruct a robust phylogeny of Photinia and its close allies to test the monophyly of the currently recognized genera, especially Photinia and Stranvaesia, and the hybrid origin hypothesis of Photinia bodinieri. This study employs complete plastomes and the entire nuclear ribosomal DNA (nrDNA) repeats assembled from the genome skimming approach with a broad taxon sampling of 81 species in 30 genera of Rosaceae, especially Maleae. Based on three datasets, including the whole plastome, coding sequence, and nrDNA repeats, the results of maximum likelihood and Bayesian inference analyses showed that the previously circumscribed Stranvaesia and Photinia were each non-monophyletic. Six clades have been recovered herein within Photinia and its allied genera: Aronia, Heteromeles, Photinia s.s., Pourthiaea, Stranvaesia, and a new genus Phippsiomeles consisting of the Central American species formerly placed in Photinia. The strong conflicts between the plastome and nrDNA phylogenies of Phippsiomeles and Stranvaesia tomentosa suggest the possibility that they may have each originated involving hybridization events, while no incongruence among datasets was detected to support the hybrid origin of Photinia bodinieri. We provide 12 new combinations, to transfer eight taxa of the New World Photinia into Phippsiomeles and clarify the generic placements of several species of Photinia and Stranvaesia

Comparison of Polyacetylene Content in Organically and Conventionally Grown Carrots Using a Fast Ultrasonic Liquid Extraction Method

A rapid and sensitive analytical method for quantification of polyacetylenes in carrot roots was developed. The traditional extraction method (stirring) was compared to a new ultrasonic liquid processor (ULP)-based methodology using high-performance liquid chromatography−ultraviolet (HPLC−UV) and mass spectrometry (MS) for identification and quantification of three polyacetylenes. ULP was superior because a significant reduction in extraction time and improved extraction efficiencies were obtained. After optimization, the ULP method showed good selectivity, precision [relative standard deviations (RSDs) of 2.3−3.6%], and recovery (93% of falcarindiol) of the polyacetylenes. The applicability of the method was documented by comparative analyses of carrots grown organically or conventionally in a 2 year field trial study. The average concentrations of falcarindiol, falcarindiol-3-acetate, and falcarinol in year 1 were 222, 30, and 94 μg of falcarindiol equiv/g of dry weight, respectively, and 3−15% lower in year 2. The concentrations were not significantly influenced by the growth system, but a significant year−year variation was observed for falcarindiol-3-acetate