Pharmacophores such as hydroxyethylamine (HEA) and phthalimide (PHT) have been identified as potential synthons for the development of compounds against various parasitic infections. In order to further advance our progress, we conducted an experiment utilising a collection of PHT and HEA derivatives through phenotypic screening against a diverse set of protist parasites. This approach led to the identification of a number of compounds that exhibited significant effects on the survival of Entamoeba histolytica, Trypanosoma brucei, and multiple life-cycle stages of Leishmania spp. The Leishmania hits were pursued due to the pressing necessity to expand our repertoire of reliable, cost-effective, and efficient medications for the treatment of leishmaniases. Antileishmanials must possess the essential capability to efficiently penetrate the host cells and their compartments in the disease context, to effectively eliminate the intracellular parasite. Hence, we performed a study to assess the effectiveness of eradicating L. infantum intracellular amastigotes in a model of macrophage infection. Among eleven L. infantum growth inhibitors with low-micromolar potency, PHT-39, which carries a trifluoromethyl substitution, demonstrated the highest efficacy in the intramacrophage assay, with an EC50 of 1.2 +/- 3.2 μM. Cytotoxicity testing of PHT-39 in HepG2 cells indicated a promising selectivity of over 90-fold. A chemogenomic profiling approach was conducted using an orthology-based method to elucidate the mode of action of PHT-39. This genome-wide RNA interference library of T. brucei identified sensitivity determinants for PHT-39, which included a P-type ATPase that is crucial for the uptake of miltefosine and amphotericin, strongly indicating a shared route for cellular entry. Notwithstanding the favourable properties and demonstrated efficacy in the Plasmodium berghei infection model, PHT-39 was unable to eradicate L. major infection in a murine infection model of cutaneous leishmaniasis. Currently, PHT-39 is undergoing derivatization to optimize its pharmacological characteristics.
- MeSH
- amfotericin B terapeutické užití MeSH
- antiprotozoální látky * farmakologie terapeutické užití MeSH
- ftalimidy farmakologie terapeutické užití MeSH
- Leishmania infantum * MeSH
- Leishmania * MeSH
- leishmanióza kožní * parazitologie MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
A series of triterpenoid pyrones was synthesized and subsequently modified to introduce phthalimide or phthalate moieties into the triterpenoid skeleton. These compounds underwent in vitro cytotoxicity screening, revealing that a subset of six compounds exhibited potent activity, with IC50 values in the low micromolar range. Further biological evaluations, including Annexin V and propidium iodide staining experiment revealed, that all compounds induce selective apoptosis in cancer cells. Measurements of mitochondrial potential, cell cycle analysis, and the expression of pro- and anti-apoptotic proteins confirmed, that apoptosis was mediated via the mitochondrial pathway. These findings were further supported by cell cycle modulation and DNA/RNA synthesis studies, which indicated a significant increase in cell accumulation in the G0/G1 phase and a marked reduction in S-phase cells, alongside a substantial inhibition of DNA synthesis. The activation of caspase-3 and the cleavage of PARP, coupled with a decrease in the expression of Bcl-2 and Bcl-XL proteins, underscored the induction of apoptosis through the mitochondrial pathway. Given their high activity and pronounced effect on mitochondria function, trifluoromethyl pyrones 1f and 2f, and dihydrophthalimide 2h have been selected for further development.
- MeSH
- antitumorózní látky * terapeutické užití MeSH
- apoptóza MeSH
- DNA metabolismus MeSH
- ftalimidy farmakologie MeSH
- kyseliny ftalové * MeSH
- membránový potenciál mitochondrií MeSH
- mitochondrie metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory * farmakoterapie MeSH
- pyrony farmakologie MeSH
- triterpeny * farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
Constant emergence of drug-resistant Plasmodium falciparum warrants urgent need for effective and inexpensive drugs. Herein, phthalimide (Pht) analogs possessing the bioactive scaffolds, benzimidazole and 1,2,3-triazole, were evaluated for in vitro and in vivo anti-plasmodial activity without any apparent hemolysis, or cytotoxicity. Analogs 4(a-e) inhibited the growth of 3D7 and RKL-9 strains at submicromolar concentrations. Defects were observed during parasite egress from or invasion of the red blood cells. Mitochondrial membrane depolarization was measured as one of the causes of cell death. Phts 4(a-e) in combination with artemisinin exhibited two-to three-fold increased efficacy. Biophysical and biochemical analysis suggest that Pht analogs mediate plasmodial growth inhibition by interacting with tubulin protein of the parasite. Lastly, Phts 4(a-e) significantly decreased parasitemia and extended host survival in murine model Plasmodium berghei ANKA infection. Combined, the data indicate that Pht analogs should be further explored, which could offer novel value to the antimalarial drug development pipeline.
- MeSH
- antimalarika * chemie MeSH
- ftalimidy chemie farmakologie MeSH
- malárie * farmakoterapie parazitologie MeSH
- myši MeSH
- Plasmodium berghei MeSH
- Plasmodium falciparum MeSH
- tubulin MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, β-secretase and β-amyloid inhibitory activities. In vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50 values ranging from 0.83 μM to 19.18 μM. The target compounds displayed inhibition of human β-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50 μM concentration. Among these compounds, two multifunctional agents (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide] and 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50 = 0.83 μM) and inhibitory activity against hBACE1 (33.61% at 50 μM). Compound 52 is a selective AChE inhibitor (IC50 AChE = 6.47 μM) with BACE1 inhibitory activity (26.3% at 50 μM) and it displays the most significant Aβ anti-aggregating properties among all the obtained compounds (39% at 10 μM). Kinetic and molecular modeling studies indicate that 26 may act as non-competitive AChE inhibitor able to interact with both catalytic and peripheral active site of the enzyme.
- MeSH
- aminy chemie farmakologie MeSH
- amyloidní beta-protein metabolismus MeSH
- cholinesterasy metabolismus MeSH
- ftalimidy chemická syntéza chemie farmakologie MeSH
- hematoencefalická bariéra účinky léků MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory enzymů chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- patologická konformace proteinů MeSH
- peptidové fragmenty metabolismus MeSH
- racionální návrh léčiv MeSH
- sacharin chemická syntéza chemie farmakologie MeSH
- sekretasy metabolismus MeSH
- systémy cílené aplikace léků MeSH
- vazba proteinů účinky léků MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- analýza přežití MeSH
- dexamethason aplikace a dávkování farmakologie MeSH
- dospělí MeSH
- ftalimidy aplikace a dávkování farmakologie MeSH
- inhibitory angiogeneze aplikace a dávkování MeSH
- inhibitory proteas aplikace a dávkování farmakologie MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- mnohočetný myelom * farmakoterapie patologie MeSH
- placeba aplikace a dávkování MeSH
- přežití po terapii bez příznaků nemoci MeSH
- protokoly antitumorózní kombinované chemoterapie aplikace a dávkování farmakologie MeSH
- sloučeniny boru aplikace a dávkování farmakologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- randomizované kontrolované studie MeSH
Sixteen new phthalimide derivatives were synthesized and evaluated for their in vitro anti-microbial, anti-oxidant and anti-inflammatory activities. The cytotoxicity for all synthesized compounds was also determined in cancer cell lines and in normal human cells. None of the target derivatives had any cytotoxic activity. (ZE)-2-[4-(1-Hydrazono-ethyl) phenyl]isoindoline-1,3-dione (12) showed remarkable anti-microbial activity. Its activity against Bacillus subtilis was 133%, 106% and 88.8% when compared with the standard antibiotics ampicillin, cefotaxime and gentamicin, respectively. Compound 12 also showed its highest activities in Gram negative bacteria against Pseudomonas aeruginosa where the percentage activities were 75% and 57.6% when compared sequentially with the standard antibiotics cefotaxime and gentamicin. It was also found that the compounds 2-[4-(4-ethyl-3-methyl-5-thioxo-1,2,4-triazolidin-3-yl)phenyl]isoindoline-1,3-dione (13b) and 2-[4-(3-methyl-5-thioxo-4-phenyl-1,2,4-triazolidin-3-yl)phenyl]isoindoline-1,3-dione (13c) had anti-oxidant activity. 4-(N'-{1-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenyl]-ethylidene}-hydrazino)-benzenesulfonamide (17c) showed the highest in vitro anti-inflammatory activity of the tested compounds (a decrease of 32%). To determine the mechanism of the anti-inflammatory activity of 17c, a docking study was carried out on the COX-2 enzyme. The results confirmed that 17c had a higher binding energy score (-17.89 kcal/mol) than that of the ligand celecoxib (-17.27 kcal/mol).
- MeSH
- antiflogistika chemická syntéza farmakologie MeSH
- antiinfekční látky chemická syntéza farmakologie MeSH
- antioxidancia chemická syntéza farmakologie MeSH
- Bacteria účinky léků MeSH
- endoteliální buňky pupečníkové žíly (lidské) účinky léků metabolismus MeSH
- ftalimidy chemická syntéza farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární modely MeSH
- nádorové buňky kultivované MeSH
- nádory farmakoterapie patologie MeSH
- NF-kappa B metabolismus MeSH
- proliferace buněk účinky léků MeSH
- racionální návrh léčiv * MeSH
- reaktivní formy kyslíku metabolismus MeSH
- techniky in vitro MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
Intercellular flow of the phytohormone auxin underpins multiple developmental processes in plants. Plant-specific pin-formed (PIN) proteins and several phosphoglycoprotein (PGP) transporters are crucial factors in auxin transport-related development, yet the molecular function of PINs remains unknown. Here, we show that PINs mediate auxin efflux from mammalian and yeast cells without needing additional plant-specific factors. Conditional gain-of-function alleles and quantitative measurements of auxin accumulation in Arabidopsis and tobacco cultured cells revealed that the action of PINs in auxin efflux is distinct from PGP, rate-limiting, specific to auxins, and sensitive to auxin transport inhibitors. This suggests a direct involvement of PINs in catalyzing cellular auxin efflux.
- MeSH
- ABC transportéry genetika metabolismus MeSH
- Arabidopsis cytologie fyziologie metabolismus růst a vývoj MeSH
- biologický transport MeSH
- buněčná membrána metabolismus MeSH
- financování organizované MeSH
- ftalimidy farmakologie MeSH
- gravitropismus MeSH
- HeLa buňky MeSH
- kinetika MeSH
- kořeny rostlin fyziologie MeSH
- kultivované buňky MeSH
- kyseliny indoloctové metabolismus MeSH
- kyseliny naftalenoctové metabolismus MeSH
- lidé MeSH
- membránové transportní proteiny genetika metabolismus MeSH
- mutace MeSH
- proteiny huseníčku genetika metabolismus MeSH
- Saccharomyces cerevisiae genetika MeSH
- tabák MeSH
- transfekce MeSH
- transformace genetická MeSH
- Check Tag
- lidé MeSH
- MeSH
- fixní kombinace léků farmakologie chemie MeSH
- ftalimidy farmakologie chemie MeSH
- hodnocení léčiv MeSH
- krevní a imunitní systémy účinky léků MeSH
- myši MeSH
- nádory farmakoterapie patologie MeSH
- sloučeniny dusíkatého yperitu farmakologie chemie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
