Publications by authors named "Marcel Kaiser"

392 Publications

Identification of Antiprotozoal Compounds from   L. by PLS-Prediction.

Molecules 2021 Oct 13;26(20). Epub 2021 Oct 13.

Institute of Pharmaceutical Biology and Phytochemistry (IPBP), PharmaCampus, University of Münster, Corrensstraße 48, D-48149 Münster, Germany.

Various -triterpene alkaloids of () L. have shown remarkable in vitro activity against the causative agents of tropical malaria and East African sleeping sickness. To identify further antiprotozoal compounds of this plant, 20 different fractions of . L., exhibiting a wide range of in vitro bioactivity, were analyzed by UHPLC/+ESI-QqTOF-MS/MS. The analytical profiles were investigated by partial least squares regression (PLS) for correlations between the intensity of LC/MS signals, bioactivity and cytotoxicity. The resulting models highlighted several compounds as mainly responsible for the antiprotozoal activity and thus, worthwhile for subsequent isolation. These compounds were dereplicated based on their mass spectra in comparison with isolated compounds recently reported by us and with literature data. Moreover, an estimation of the cytotoxicity of the highlighted compounds was derived from an additional PLS model in order to identify plant constituents with strong selectivity. In conclusion, high levels of antitrypanosomal and antiplasmodial activity were predicted for eight and four compounds, respectively. These include three hitherto unknown constituents of . L., presumably new natural products.
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http://dx.doi.org/10.3390/molecules26206181DOI Listing
October 2021

A Modular Approach to the Antifungal Sphingofungin Family: Concise Total Synthesis of Sphingofungin A and C.

Angew Chem Int Ed Engl 2021 Oct 22. Epub 2021 Oct 22.

Leibniz-Institut fur Naturstoff-Forschung und Infektionsbiologie eV Hans-Knoll-Institut, Chemical Biology, Beutenbergstr. 11a, 07745, Deutschland, 07745, Jena, GERMANY.

Sphingofungins are fungal natural products known to inhibit the biosynthesis of sphingolipids which play pivotal roles in various cell functions. Here, we report a short and flexible synthetic approach towards the sphingofungin family. Key step of the synthesis was a decarboxylative cross-coupling reaction of chiral sulfinyl imines with a functionalized tartaric acid derivative, which yielded the core motive of sphingofungins carrying four consecutive stereocenters and a terminal double bond. Subsequent metathesis reaction allowed for the introduction of different side chains of choice resulting in a total of eight sphingofungins, including for the first time sphingofungin C (eight steps from commercially available protected tartaric acid with an overall yield of 6%) and sphingofungin A (ten steps). All newly synthesized derivatives were tested for their antifungal, cell proliferative and antiparasitic activity unraveling their structure-activity relations.
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http://dx.doi.org/10.1002/anie.202112616DOI Listing
October 2021

8-Amino-6-Methoxyquinoline-Tetrazole Hybrids: Impact of Linkers on Antiplasmodial Activity.

Molecules 2021 Sep 12;26(18). Epub 2021 Sep 12.

Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstraße 1, A-8010 Graz, Austria.

A new series of compounds was prepared from 6-methoxyquinolin-8-amine or its -(2-aminoethyl) analogue via Ugi-azide reaction. Their linkers between the quinoline and the -butyltetrazole moieties differ in chain length, basicity and substitution. Compounds were tested for their antiplasmodial activity against NF54 as well as their cytotoxicity against L-6-cells. The activity and the cytotoxicity were strongly influenced by the linker and its substitution. The most active compounds showed good activity and promising selectivity.
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http://dx.doi.org/10.3390/molecules26185530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470823PMC
September 2021

Hygroline derivatives from Schizanthus tricolor and their anti-trypanosomatid and antiplasmodial activities.

Phytochemistry 2021 Sep 23;192:112957. Epub 2021 Sep 23.

School of Pharmaceutical Sciences, University of Geneva, 1211, Geneva, 4, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211, Geneva, 4, Switzerland.

Chemical investigation of the alkaloid extract of the aerial parts of Schizanthus tricolor led to the targeted isolation of 26 hygroline derivatives of which 20 were fully characterized. They have not yet been described in the literature and their structures were established by 1D and 2D NMR, UV and IR spectroscopy, and HRESIMS. The configuration was determined by Gauge-Independent Atomic Orbital NMR chemical shift calculations supported by the advanced statistical method DP4 plus, vibrational circular dichroism, and measurement of optical rotation. Their anti-trypanosomatid, antiplasmodial and cytotoxic activities were measured. Several compounds exhibited low micromolar activity against Plasmodium falciparum. None of the identified molecules was cytotoxic.
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http://dx.doi.org/10.1016/j.phytochem.2021.112957DOI Listing
September 2021

Mutasynthesis of Physostigmines in .

Org Lett 2021 08 6;23(16):6563-6567. Epub 2021 Aug 6.

Department of Biochemical and Chemical Engineering, TU Dortmund University, Dortmund, 44227 Nordrhein-Westfalen, Germany.

The alkaloid physostigmine is an approved anticholinergic drug and an important lead structure for the development of novel therapeutics. Using a complementary approach that merged chemical synthesis with pathway refactoring, we produced a series of physostigmine analogues with altered specificity and toxicity profiles in the heterologous host . The compounds that were generated by applying a simple feeding strategy include the promising drug candidate phenserine, which was previously accessible only by total synthesis.
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http://dx.doi.org/10.1021/acs.orglett.1c02374DOI Listing
August 2021

Enantiospecific antitrypanosomal in vitro activity of eflornithine.

PLoS Negl Trop Dis 2021 07 12;15(7):e0009583. Epub 2021 Jul 12.

Unit for Pharmacokinetics and Drug Metabolism, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

The polyamine synthesis inhibitor eflornithine is a recommended treatment for the neglected tropical disease Gambian human African trypanosomiasis in late stage. This parasitic disease, transmitted by the tsetse fly, is lethal unless treated. Eflornithine is administered by repeated intravenous infusions as a racemic mixture of L-eflornithine and D-eflornithine. The study compared the in vitro antitrypanosomal activity of the two enantiomers with the racemic mixture against three Trypanosoma brucei gambiense strains. Antitrypanosomal in vitro activity at varying drug concentrations was analysed by non-linear mixed effects modelling. For all three strains, L-eflornithine was more potent than D-eflornithine. Estimated 50% inhibitory concentrations of the three strains combined were 9.1 μM (95% confidence interval [8.1; 10]), 5.5 μM [4.5; 6.6], and 50 μM [42; 57] for racemic eflornithine, L-eflornithine and D-eflornithine, respectively. The higher in vitro potency of L-eflornithine warrants further studies to assess its potential for improving the treatment of late-stage Gambian human African trypanosomiasis.
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http://dx.doi.org/10.1371/journal.pntd.0009583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297939PMC
July 2021

Niclosamide Is Active In Vitro against Mycetoma Pathogens.

Molecules 2021 Jun 30;26(13). Epub 2021 Jun 30.

Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland.

Redox-active drugs are the mainstay of parasite chemotherapy. To assess their repurposing potential for eumycetoma, we have tested a set of nitroheterocycles and peroxides in vitro against two isolates of , the main causative agent of eumycetoma in Sudan. All the tested compounds were inactive except for niclosamide, which had minimal inhibitory concentrations of around 1 µg/mL. Further tests with niclosamide and niclosamide ethanolamine demonstrated in vitro activity not only against but also against spp., causative agents of actinomycetoma, with minimal inhibitory concentrations below 1 µg/mL. The experimental compound MMV665807, a related salicylanilide without a nitro group, was as active as niclosamide, indicating that the antimycetomal action of niclosamide is independent of its redox chemistry (which is in agreement with the complete lack of activity in all other nitroheterocyclic drugs tested). Based on these results, we propose to further evaluate the salicylanilides, niclosamidein particular, as drug repurposing candidates for mycetoma.
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http://dx.doi.org/10.3390/molecules26134005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271592PMC
June 2021

Boswellic Acids Show In Vitro Activity against .

Molecules 2021 Jun 15;26(12). Epub 2021 Jun 15.

Institute of Pharmaceutical Biology and Phytochemistry, University of Münster, Pharma Campus-Corrensstrasse 48, D-48149 Münster, Germany.

In continuation of our search for leads from medicinal plants against protozoal pathogens, we detected antileishmanial activity in polar fractions of a dichloromethane extract from resin. 11-keto-β-boswellic acid (KBA) could be isolated from these fractions and was tested in vitro against axenic amastigotes along with five further boswellic acid derivatives. 3--acetyl-11-keto-β-boswellic acid (AKBA) showed the strongest activity with an IC value of 0.88 µM against axenic amastigotes but was inactive against intracellular amastigotes in murine macrophages.
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http://dx.doi.org/10.3390/molecules26123651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232742PMC
June 2021

Antiprotozoal -Triterpene Alkaloids from L.

Antibiotics (Basel) 2021 Jun 10;10(6). Epub 2021 Jun 10.

Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus Corrensstraße 48, D-48149 Münster, Germany.

Malaria and human African trypanosomiasis (HAT; sleeping sickness) are life-threatening tropical diseases caused by protozoan parasites. Due to limited therapeutic options, there is a compelling need for new antiprotozoal agents. In a previous study, O-tigloylcyclovirobuxeine-B was recovered from a . L. (common box; Buxaceae) leaf extract by bioactivity-guided isolation. This -cycloartane alkaloid was identified as possessing strong and selective in vitro activity against the causative agent of malaria tropica, (). The purpose of this study is the isolation of additional alkaloids from . L. to search for further related compounds with strong antiprotozoal activity. In conclusion, 25 alkaloids were obtained from . L., including eight new natural products and one compound first described for this plant. The structure elucidation was accomplished by UHPLC/+ESI-QqTOF-MS/MS and NMR spectroscopy. The isolated alkaloids were tested against and (), the causative agent of East African sleeping sickness. To assess their selectivity, cytotoxicity against mammalian cells (L6 cell line) was tested as well. Several of the compounds displayed promising in vitro activity against the pathogens in a sub-micromolar range with concurrent high selectivity indices (SI). Consequently, various alkaloids from . L. have the potential to serve as a novel antiprotozoal lead structure.
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http://dx.doi.org/10.3390/antibiotics10060696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228141PMC
June 2021

Investigation of thiazolyl-benzothiophenamides as potential agents for African sleeping sickness.

RSC Med Chem 2020 Dec 23;11(12):1413-1422. Epub 2020 Sep 23.

School of Chemistry and Molecular Bioscience, and Molecular Horizons Research Institute, University of Wollongong Wollongong 2522 NSW Australia

African sleeping sickness is a potentially fatal neglected disease affecting sub-Saharan Africa. High-throughput screening identified the thiazolyl-benzothiophenamide to be active against the causative parasite, . This work establishes structure-activity relationships of , guiding the design of second generation derivatives. After screening against the clinically relevant species , the derivative was identified as a suitable candidate for further investigation.
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http://dx.doi.org/10.1039/d0md00277aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126881PMC
December 2020

Synthesis, in vitro antiprotozoal activity, molecular docking and molecular dynamics studies of some new monocationic guanidinobenzimidazoles.

Eur J Med Chem 2021 Oct 24;221:113545. Epub 2021 May 24.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06100, Tandogan, Ankara, Turkey. Electronic address:

A series of monocationic new guanidinobenzimidazole derivatives were prepared in a four step process starting from 2-nitro-1,4-phenylendiamine. Their antiparasitic activity against Plasmodium falciparum, Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani were evaluated in vitro. Two out of 20 tested monocationic compounds (7, 14) showed close activity with reference drug chloroquine against P. Falciparum. To understand the interactions between DNA minor groove and in vitro active compounds (7, 14) molecular docking studies were carried out. Stability and binding energies of DNA-ligand complexes formed by DNA with compounds 7 and 14 were measured by molecular dynamics simulations throughout 200 ns time. Root mean square deviation (RMSD) values of the ligands remained stable below 0.25 mm and root mean square fluctuation (RMSF) values of the active site residues with which it interacted decreased compared to the apo form. All compounds exhibited theoretical absorption, distribution, metabolism and excretion (ADME) profiles conforming to Lipinski's and Ghose's restrictive rules.
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http://dx.doi.org/10.1016/j.ejmech.2021.113545DOI Listing
October 2021

L.: Antitrypanosomal Activity and Active Constituents against .

Molecules 2021 May 27;26(11). Epub 2021 May 27.

Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus, Corrensstr. 48, D-48149 Münster, Germany.

As part of our studies on antiprotozoal activity of approved herbal medicinal products, we previously found that a commercial tincture from L. (common Sage, Lamiaceae) possesses high activity against , causative agent of East African Human Trypanosomiasis. We have now investigated in detail the antitrypanosomal constituents of this preparation. A variety of fractions were tested for antitrypanosomal activity and analyzed by UHPLC/+ESI QqTOF MS. The resulting data were used to generate a partial least squares (PLS) regression model that highlighted eight particular constituents that were likely to account for the major part of the bioactivity. These compounds were then purified and identified and their activity against the pathogen tested. All identified compounds (one flavonoid and eight diterpenes) displayed significant activity against , in some cases higher than that of the total tincture. From the overall results, it can be concluded that the antitrypanosomal activity of L. is, for the major part, caused by abietane-type diterpenes of the rosmanol/rosmaquinone group.
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http://dx.doi.org/10.3390/molecules26113226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199030PMC
May 2021

Diaryl Ureas as an Antiprotozoal Chemotype.

ACS Infect Dis 2021 06 10;7(6):1578-1583. Epub 2021 May 10.

College of Pharmacy, University of Nebraska Medical Center, 986125 Nebraska Medical Center, Omaha, Nebraska 68198-6125, United States.

We now describe the physicochemical profiling, ADME, and antiparasitic activity of eight ,-diarylureas to assess their potential as a broad-spectrum antiprotozoal chemotype. Chromatographic LogD values ranged from 2.5 to 4.5; kinetic aq. solubilities were ≤6.3 μg/mL, and plasma protein binding ranged from 95 to 99%. All of the compounds had low intrinsic clearance values in human, but not mouse, liver microsomes. Although no ,-diarylurea had submicromolar potency against , two had submicromolar potencies against and , and five had submicromolar potencies against . appeared to be the most susceptible to growth inhibition by this compound series. Most of the ,-diarylureas had antiprotozoal selectivities ≥10. One ,-diarylurea had demonstrable activity in mouse models of malaria and toxoplasmosis.
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http://dx.doi.org/10.1021/acsinfecdis.1c00135DOI Listing
June 2021

New Acyl Derivatives of 3-Aminofurazanes and Their Antiplasmodial Activities.

Pharmaceuticals (Basel) 2021 Apr 27;14(5). Epub 2021 Apr 27.

Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstraße 1, A-8010 Graz, Austria.

An -acylated furazan-3-amine of a Medicines for Malaria Venture (MMV) project has shown activity against different strains of . Seventeen new derivatives were prepared and tested in vitro for their activities against blood stages of two strains of . Several structure-activity relationships were revealed. The activity strongly depended on the nature of the acyl moiety. Only benzamides showed promising activity. The substitution pattern of their phenyl ring affected the activity and the cytotoxicity of compounds. In addition, physicochemical parameters were calculated (log P, log D, ligand efficiency) or determined experimentally (permeability) via a PAMPA. The -(4-(3,4-diethoxyphenyl)-1,2,5-oxadiazol-3-yl)-3-(trifluoromethyl)benzamide possessed good physicochemical properties and showed high antiplasmodial activity against a chloroquine-sensitive strain (IC(NF54) = 0.019 µM) and even higher antiplasmodial activity against a multiresistant strain (IC(K) = 0.007 µM). Compared to the MMV compound, the permeability and the activity against the multiresistant strain were improved.
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http://dx.doi.org/10.3390/ph14050412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145535PMC
April 2021

Synthesis and Biological Evaluation of Natural-Product-Inspired, Aminoalkyl-Substituted 1-Benzopyrans as Novel Antiplasmodial Agents.

J Med Chem 2021 05 26;64(9):6397-6409. Epub 2021 Apr 26.

Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.

Herein, relationships between the structures of 1-aminoethyl-substituted chromenes and their antimalarial activities were thoroughly investigated. At first, the methyl moiety in the side chain was removed to eliminate chirality. The hydrogenation state of the benzopyran system, the position of the phenolic OH moiety, and the distance of the basic amino moiety toward both aromatic rings were varied systematically. 1-Benzopyran-5-ol (IC = 10 nM), 1-benzopyran-7-ol (IC = 38 nM), and the aminoalcohol (IC = 17 nM) displayed antiplasmodial activity with IC values below 50 nM. To identify the mechanism of action, inhibition of three key enzymes by was investigated. was not able to reduce the number of in erythrocytes of mice. This low in vivo activity was explained by fast clearance from blood plasma combined with rapid biotransformation of . Three main metabolites of were identified by liquid chromatography-mass spectrometry (LC-MS) methods.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00483DOI Listing
May 2021

Spirombandakamine A and Cyclombandakamines A and A, Polycyclic Naphthylisoquinoline Dimers, with Antiprotozoal Activity, from a Congolese Plant.

J Nat Prod 2021 04 12;84(4):1335-1344. Epub 2021 Apr 12.

Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany.

Spirombandakamine A () is only the third known naphthylisoquinoline dimer with a spiro-fused novel molecular framework and the first such representative to possess a relative -configuration at the two chiral centers in both tetrahydroisoquinoline subunits. It was found in the leaves of a botanically as yet unidentified Congolese plant, which is morphologically closely related to the Central African taxon . Likewise isolated were the new cyclombandakamines A () and A (), which belong to another most recently discovered type of unusual oxygen-bridged naphthylisoquinoline dimers and two previously described "open-chain" analogues, mbandakamines C () and D (). The full absolute stereostructures of these compounds were assigned by combining spectroscopic, chemical, and chiroptical methods. Preliminary biomimetic investigations indicated that both spirombandakamine- and cyclombandakamine-type dimers result from the oxidation of their open-chain mbandakamine-type congeners. The new dimeric alkaloids - displayed potent growth-inhibitory activity against , the protozoal pathogen causing malaria, and moderate effects on , the parasite responsible for African sleeping sickness.
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http://dx.doi.org/10.1021/acs.jnatprod.1c00063DOI Listing
April 2021

Neue Parameter für die Wirkstofftestung gegen .

Biospektrum (Heidelb) 2021 23;27(2):168-170. Epub 2021 Mar 23.

Universität Basel Schweizerisches Tropen- und Public Health-Institut (Swiss TPH), Socinstraße 57, CH-4051 Basel, Schweiz.

Chagas disease is a zoonosis caused by and transmitted by triatomine bugs. Autochthonous to Latin America, Chagas disease has spread globally through travel and migration. New drugs are needed urgently, in particular drugs that cure the chronic stage. This is where high-content imaging makes a key contribution: assays with fluorescent parasites in cell culture allow to determine pharmacodynamic parameters and to better assess the antichagasic potential of new molecules.
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http://dx.doi.org/10.1007/s12268-021-1554-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985589PMC
March 2021

Combination With Tomatidine Improves the Potency of Posaconazole Against .

Front Cell Infect Microbiol 2021 4;11:617917. Epub 2021 Mar 4.

Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology, Basel, Switzerland.

Azoles such as posaconazole (Posa) are highly potent against . However, when tested in chronic Chagas disease patients, a high rate of relapse after Posa treatment was observed. It appears that inhibition of cytochrome CYP51, the target of azoles, does not deliver sterile cure in monotherapy. Looking for suitable combination partners of azoles, we have selected a set of inhibitors of sterol and sphingolipid biosynthetic enzymes. A small-scale phenotypic screening was conducted against the proliferative forms of , extracellular epimastigotes and intracellular amastigotes. Against the intracellular, clinically relevant forms, four out of 15 tested compounds presented higher or equal activity as benznidazole (Bz), with EC values ≤2.2 μM. Ro48-8071, an inhibitor of lanosterol synthase (ERG7), and the steroidal alkaloid tomatidine (TH), an inhibitor of C-24 sterol methyltransferase (ERG6), exhibited the highest potency and selectivity indices (SI = 12 and 115, respectively). Both were directed to combinatory assays using fixed-ratio protocols with Posa, Bz, and fexinidazole. The combination of TH with Posa displayed a synergistic profile against amastigotes, with a mean ΣFICI value of 0.2. assays using an acute mouse model of infection demonstrated lack of antiparasitic activity of TH alone in doses ranging from 0.5 to 5 mg/kg. As observed , the best combo proportion was the ratio 3 TH:1 Posa. The combination of Posa at 1.25 mpk plus TH at 3.75 mpk displayed suppression of peak parasitemia of 80% and a survival rate of 60% in the acute infection model, as compared to 20% survival for Posa at 1.25 mpk alone and 40% for Posa at 10 mpk alone. These initial results indicate a potential for the combination of posaconazole with tomatidine against .
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http://dx.doi.org/10.3389/fcimb.2021.617917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970121PMC
July 2021

Antiprotozoal Structure-Activity Relationships of Synthetic Leucinostatin Derivatives and Elucidation of their Mode of Action.

Angew Chem Int Ed Engl 2021 07 10;60(28):15613-15621. Epub 2021 May 10.

Institute of Chemistry and Biotechnology, Center for Organic and Medicinal Chemistry, Zurich University of Applied Sciences (ZHAW), Einsiedlerstrasse 31, 8820, Wädenswil, Switzerland.

Leucinostatin A is one of the most potent antiprotozoal compounds ever described, but little was known on structure-activity relationships (SAR). We used Trypanosoma brucei as a protozoal model organism to test synthetically modified derivatives, resulting in simplified but equally active compounds 2 (ZHAWOC6025) and 4 (ZHAWOC6027), which were subsequently modified in all regions of the molecule to gain an in-depth SAR understanding. The antiprotozoal SAR matched SAR in phospholipid liposomes, where membrane integrity, leaking, and dynamics were studied. The mode of action is discussed based on a structure-activity analysis of derivatives in efficacy, ultrastructural studies in T. brucei, and artificial membrane models, mimicking membrane stability and membrane potential. The main site of antiprotozoal action of natural and synthetic leucinostatins lies in the destabilization of the inner mitochondrial membrane, as demonstrated by ultrastructural analysis, electron microscopy and mitochondrial staining. Long-time sublethal exposure of T. brucei (200 passages) and siRNA screening of 12'000 mutants showed no signs of resistance development to the synthetic derivatives.
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http://dx.doi.org/10.1002/anie.202102153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360131PMC
July 2021

Quest for a potent antimalarial drug lead: Synthesis and evaluation of 6,7-dimethoxyquinazoline-2,4-diamines.

Bioorg Med Chem 2021 03 16;33:116018. Epub 2021 Jan 16.

Synstar Japan Co., Ltd., 2-9-46 Sakaecho, Odawara, Kanagawa 250-0011, Japan. Electronic address:

Quinazolines have long been known to exert varied pharmacologic activities that make them suitable for use in treating hypertension, viral infections, tumors, and malaria. Since 2014, we have synthesized approximately 150 different 6,7-dimethoxyquinazoline-2,4-diamines and evaluated their antimalarial activity via structure-activity relationship studies. Here, we summarize the results and report the discovery of 6,7-dimethoxy-N-(1-phenylethyl)-2-(pyrrolidin-1-yl)quinazolin-4-amine (20, SSJ-717), which exhibits high antimalarial activity as a promising antimalarial drug lead.
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http://dx.doi.org/10.1016/j.bmc.2021.116018DOI Listing
March 2021

The Alkaloid-Enriched Fraction of (Buxaceae) Shows Prominent Activity against .

Molecules 2021 Jan 23;26(3). Epub 2021 Jan 23.

Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus, Corrensstr. 48, D-48149 Münster, Germany.

In the course of our studies on antiprotozoal natural products and following our recent discovery that certain aminosteroids and aminocycloartanoid compounds from A. DC. (Apocynaceae) and L. (Buxaceae), respectively, are strong and selective antitrypanosomal agents, we have extended these studies to another plant, related to the latter-namely, Sieb. and Zucc. (Buxaceae). This species is known to contain aminosteroids similar to those of and structurally related to the aminocycloartanoids of . The dicholoromethane extract obtained from aerial parts of and, in particular, its alkaloid fraction obtained by acid-base partitioning showed prominent activity against . Activity-guided fractionation along with extended UHPLC-(+)ESI QTOF MS analyses coupled with partial least squares (PLS) regression modelling relating the analytical profiles of various fractions with their bioactivity against highlighted eighteen constituents likely responsible for the antitrypanosomal activity. Detailed analysis of their (+)ESI mass spectral fragmentation allowed identification of four known constituents of as well as structural characterization of ten further amino-/amidosteroids not previously reported from this plant.
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http://dx.doi.org/10.3390/molecules26030591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865568PMC
January 2021

An Alba-domain protein required for proteome remodelling during trypanosome differentiation and host transition.

PLoS Pathog 2021 01 25;17(1):e1009239. Epub 2021 Jan 25.

Institute of Cell Biology, University of Bern, Bern, Switzerland.

The transition between hosts is a challenge for digenetic parasites as it is unpredictable. For Trypanosoma brucei subspecies, which are disseminated by tsetse flies, adaptation to the new host requires differentiation of stumpy forms picked up from mammals to procyclic forms in the fly midgut. Here we show that the Alba-domain protein Alba3 is not essential for mammalian slender forms, nor is it required for differentiation of slender to stumpy forms in culture or in mice. It is crucial, however, for the development of T. brucei procyclic forms during the host transition. While steady state levels of mRNAs in differentiating cells are barely affected by the loss of Alba3, there are major repercussions for the proteome. Mechanistically, Alba3 aids differentiation by rapidly releasing stumpy forms from translational repression and stimulating polysome formation. In its absence, parasites fail to remodel their proteome appropriately, lack components of the mitochondrial respiratory chain and show reduced infection of tsetse. Interestingly, Alba3 and the closely related Alba4 are functionally redundant in slender forms, but Alba4 cannot compensate for the lack of Alba3 during differentiation from the stumpy to the procyclic form. We postulate that Alba-domain proteins play similar roles in regulating translation in other protozoan parasites, in particular during life-cycle and host transitions.
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http://dx.doi.org/10.1371/journal.ppat.1009239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861527PMC
January 2021

Activation, Structure, Biosynthesis and Bioactivity of Glidobactin-like Proteasome Inhibitors from Photorhabdus laumondii.

Chembiochem 2021 May 3;22(9):1582-1588. Epub 2021 Mar 3.

Molecular Biotechnology, Department of Biosciences, Goethe University Frankfurt, 60438, Frankfurt am Main, Germany.

The glidobactin-like natural products (GLNPs) glidobactin A and cepafungin I have been reported to be potent proteasome inhibitors and are regarded as promising candidates for anticancer drug development. Their biosynthetic gene cluster (BGC) plu1881-1877 is present in entomopathogenic Photorhabdus laumondii but silent under standard laboratory conditions. Here we show the largest subset of GLNPs, which are produced and identified after activation of the silent BGC in the native host and following heterologous expression of the BGC in Escherichia coli. Their chemical diversity results from a relaxed substrate specificity and flexible product release in the assembly line of GLNPs. Crystal structure analysis of the yeast proteasome in complex with new GLNPs suggests that the degree of unsaturation and the length of the aliphatic tail are critical for their bioactivity. The results in this study provide the basis to engineer the BGC for the generation of new GLNPs and to optimize these natural products resulting in potential drugs for cancer therapy.
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http://dx.doi.org/10.1002/cbic.202100014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248439PMC
May 2021

Unusual derivatives from Hypericum scabrum.

Sci Rep 2021 01 14;10(1):22181. Epub 2021 Jan 14.

Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, Evin, Tehran, Iran.

Three new compounds (1-3) with unusual skeletons were isolated from the n-hexane extract of the air-dried aerial parts of Hypericum scabrum. Compound 1 represents the first example of an esterified polycyclic polyprenylated acylphloroglucinol that features a unique tricyclo-[4.3.1.1]-undecane skeleton. Compound 2 is a fairly simple MPAP, but with an unexpected cycloheptane ring decorated with prenyl substituents, and compound 3 has an unusual 5,5-spiroketal lactone core. Their structures were determined by extensive spectroscopic and spectrometric techniques (1D and 2D NMR, HRESI-TOFMS). Absolute configurations were established by ECD calculations, and the absolute structure of 2 was confirmed by a single crystal determination. Plausible biogenetic pathways of compounds 1-3 were also proposed. The in vitro antiprotozoal activity of the compounds against Trypanosoma brucei rhodesiense and Plasmodium falciparum and cytotoxicity against rat myoblast (L6) cells were determined. Compound 1 showed a moderate activity against T. brucei and P. falciparum, with IC values of 3.07 and 2.25 μM, respectively.
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http://dx.doi.org/10.1038/s41598-020-79305-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809121PMC
January 2021

Incidence of antiepileptic drug therapy and factors associated with their prescribing in outpatients with diabetic polyneuropathy.

Prim Care Diabetes 2021 06 7;15(3):535-540. Epub 2021 Jan 7.

Epidemiology, IQVIA, Frankfurt, Germany. Electronic address:

Aims: The goal of this retrospective cohort study was to analyze the incidence of, and factors associated with the antiepileptic drug (AED) therapy in the five years following the diagnosis of diabetic polyneuropathy in patients followed in Germany.

Methods: The study included patients aged 18-80 years with an initial diagnosis of diabetic polyneuropathy in 1238 general and diabetologist practices in Germany between January 2008 and December 2017 (index date). The main outcome of the study was the incidence of the AED therapy in the five years following the diagnosis of diabetic polyneuropathy. Adjusted Cox regression analyses were conducted to investigate the association between study covariates and the incidence of the AED therapy.

Results: The present study included 48,324 patients (mean [standard deviation] age 65.8 [10.6] years, 55.6% male). Within five years of the diagnosis of diabetic polyneuropathy, 16.4% of patients were prescribed at least one AED. The three most frequent drugs were pregabalin, gabapentin, and carbamazepine. Female sex (HR = 1.22), private health insurance coverage (HR = 1.22), follow-up in a general practice (HR = 1.85), HbA1c ≥10% (HR = 1.36), previous referral to a neurological practice (HR = 1.47), previous hospital admission (HR = 1.51) and depression (HR = 1.15) were positively associated with the incidence of the AED therapy.

Conclusions: The incidence of the AED therapy was low in patients recently diagnosed with diabetic polyneuropathy in Germany. More research is warranted to understand the infrequent use of AEDs in diabetic polyneuropathy patients from this country.
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http://dx.doi.org/10.1016/j.pcd.2020.12.005DOI Listing
June 2021

Preparation of new 1,3-dibenzyl tetrahydropyridinylidene ammonium salts and their antimicrobial and anticellular activities.

Eur J Med Chem 2021 Jan 29;210:112969. Epub 2020 Oct 29.

Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstrasse 1, 8010 Graz, Austria.

New 1,3 dibenzyl -tetrahydropyridinylidene ammonium salts have been prepared from unsubstituted or N-benzylated tetrahydropyridinylidene ammonium salts. The antiplasmodial and antitrypanosomal activities as well as their cytotoxic effects were determined using microplate assays. In addition, their activities against two gram positive and two gram negative bacteria strains and a yeast strain were examined. Furthermore, anticancer effects against two cell lines were investigated. Physicochemical parameters were calculated and structure-activity-relationships discussed. One compound showed antiplasmodial activity against a multiresistant strain of Plasmodium falciparum in subnanomolar concentration. Antitrypanosomal activities were detected in low nanomolar concentrations. A single compound was active against grampositive and gramnegative bacteria, as well as yeast. One compound inhibited the growth of a HCT cell line in low concentration.
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http://dx.doi.org/10.1016/j.ejmech.2020.112969DOI Listing
January 2021

Multimorbidity Among Adult Outpatients With Type 1 Diabetes in Germany.

J Diabetes Sci Technol 2020 Oct 23:1932296820965261. Epub 2020 Oct 23.

Epidemiology, IQVIA, Frankfurt, Germany.

Aim: The aim of this cross-sectional retrospective study was to estimate the prevalence of different physical and psychiatric disorders as well as multimorbidity in outpatients with type 1 diabetes (T1D) in Germany.

Methods: A total of 6967 adult patients with T1D from 958 general or diabetologist practices in Germany between January 2015 and December 2019 from the Disease Analyzer database (IQVIA) were included. The main outcome of the study was the prevalence of different diabetes-related and nondiabetes-related disorders within 12 months prior to the last outpatient visit. Multivariate logistic regression models were fitted with multimorbidity differently defined as >2, >3, >4, and >5 different disorders as a dependent variable and age, sex, glycated hemoglobin (HbA1c) values, and insulin pump therapy as impact variables.

Results: Mean age (SD) was 45.3 (16.7) years; 42.9% were women, the mean HbA1c was 7.9% (SD: 1.4%). The most frequent disorder was arterial hypertension (31.2%), followed by dyslipidemia (26.4%), dorsalgia (20.4%), diabetic neuropathy (17.3%), and depression (14.6%). The proportion of thyroid gland disorders, retinopathy, urethritis, iron deficiency anemia, and psychiatric disorders was higher in women than in men. Hypertension and mental and behavioral disorders due to the use of tobacco were higher in men. On average, each patient was diagnosed with 3.1 different disorders. Age had the strongest association with multimorbidity, followed by HbA1c value and female sex.

Conclusion: In summary, patients with T1D are often multimorbid, and the multimorbidity is associated with higher gender, female sex, and high HbA1c values. Understanding all of these factors can help practitioners create a risk profile for every patient.
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http://dx.doi.org/10.1177/1932296820965261DOI Listing
October 2020

Pyridine-4(1)-one Alkaloids from as Antitrypanosomatid Agents.

J Nat Prod 2020 11 23;83(11):3363-3371. Epub 2020 Oct 23.

School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva 4, Switzerland.

Twelve new pyridine-4(1)-one derivatives, namely, 8-demethoxywaltherione F (), waltheriones R-V (, , , , and ), 1-methoxywaltherione O (), ()-15-hydroxywaltherione G (), (8)-8-hydroxywaltherione M (), (9,13)-2-hydroxymethylwaltherione C (), (9,10,13)-10-hydroxywaltherione C (), and ()-13-methoxywaltherione V (), as well as melovinone () and 5'-methoxywaltherione A () were isolated from the CHCl extract of the aerial parts of Their chemical structures were determined by means of a comprehensive analysis including H NMR, DEPTQ, HSQC, HMBC, H-H COSY, ROESY, and HRESIMS data. The absolute configurations were assigned via comparison of the experimental and calculated ECD data. In addition, the isolated constituents as well as the known waltheriones M-Q were evaluated for their in vitro antitrypanosomal activity. Compounds , , and as well as waltheriones M, P, and Q showed potent growth inhibition toward with IC values of 2.1, 0.8, 2.1, 1.3, 0.5, and 0.1 μM, respectively, and selectivity indices of >12, >33, >13, 5, 25, and 14. These findings further demonstrate that the waltheriones are a promising class of antichagasic compounds worthy of further investigations.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00671DOI Listing
November 2020

The discovery of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines.

Eur J Med Chem 2021 Jan 5;209:112871. Epub 2020 Oct 5.

Leicester School of Allied Health Sciences, De Montfort University, The Gateway, Leicester, LE1 9BH, UK. Electronic address:

Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense which seriously affects human health in Africa. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work herein describes the design and syntheses of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines, with compound 13, the 4-(2-methoxyphenyl)-6-(pyridine-3-yl)pyrimidin-2-amine demonstrating an IC value of 0.38 μM and a promising off-target ADME-Tox profile in vitro. In silico molecular target investigations showed rhodesain to be a putative candidate, supported by STD and WaterLOGSY NMR experiments, however, in vitro evaluation of compound 13 against rhodesain exhibited low experimental inhibition. Therefore, our reported library of drug-like pyrimidines present promising scaffolds for further antikinetoplastid drug development for both phenotypic and target-based drug discovery.
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http://dx.doi.org/10.1016/j.ejmech.2020.112871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762786PMC
January 2021

Palladium-catalysed synthesis of arylnaphthoquinones as antiprotozoal and antimycobacterial agents.

Eur J Med Chem 2020 Dec 12;207:112837. Epub 2020 Sep 12.

Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstrasse 1, A-8010, Graz, Austria. Electronic address:

Malaria and tuberculosis are still among the leading causes of death in low-income countries. The 1,4-naphthoquinone (NQ) scaffold can be found in a variety of anti-infective agents. Herein, we report an optimised, high yield process for the preparation of various 2-arylnaphthoquinones by a palladium-catalysed Suzuki reaction. All synthesised compounds were evaluated for their in-vitro antiprotozoal and antimycobacterial activity. Antiprotozoal activity was assessed against Plasmodium falciparum (P.f.) NF54 and Trypanosoma brucei rhodesiense (T.b.r.) STIB900, and antimycobacterial activity against Mycobacterium smegmatis (M.s.) mc 155. Substitution with pyridine and pyrimidine rings significantly increased antiplasmodial potency of our compounds. The 2-aryl-NQs exhibited trypanocidal activity in the nM range with a very favourable selectivity profile. (Pseudo)halogenated aryl-NQs were found to have a pronounced effect indicating inhibition of mycobacterial efflux pumps. Cytotoxicity of all compounds towards L6 cells was evaluated and the respective selectivity indices (SI) were calculated. In addition, the physicochemical parameters of the synthesised compounds were discussed.
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http://dx.doi.org/10.1016/j.ejmech.2020.112837DOI Listing
December 2020
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