Some pathogens, including parasites of the genus Trypanosoma causing Human and Animal African Trypanosomiases, cannot synthesize purines de novo and they entirely rely on the purine salvage pathway (PSP) for their nucleotide generation. Thus, their PSP enzymes are considered as promising drug targets, sparsely explored so far. Recently, a significant role of acyclic nucleoside phosphonates (ANPs) as inhibitors of key enzymes of PSP, namely of 6-oxopurine phosphoribosyltransferases (PRTs), has been discovered. Herein, we designed and synthesized two series of new ANPs branched at the C1' position as mimics of adenosine monophosphate. The novel ANPs efficaciously inhibited Trypanosoma brucei adenine PRT (TbrAPRT1) activity in vitro and it was shown that the configuration on the C1' chiral centre strongly influenced their activity: the (R)-enantiomers proved to be more potent compared to the (S)-enantiomers. Two ANPs, with Ki values of 0.39 μM and 0.57 μM, represent the most potent TbrAPRT1 inhibitors reported to date and they are an important tool to further study purine metabolism in various parasites.

• MeSH
• adeninfosforibosyltransferasa antagonisté a inhibitory   metabolismus   MeSH
• adenosinmonofosfát chemická syntéza   chemie   farmakologie   MeSH
• antiprotozoální látky chemická syntéza   chemie   farmakologie   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• molekulární struktura MeSH
• nukleosidy chemická syntéza   chemie   farmakologie   MeSH
• parazitické testy citlivosti MeSH
• Trypanosoma brucei brucei účinky léků   enzymologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH

Trypanosoma brucei parasites cause Human African Trypanosomiasis and the current drugs for its treatment are often inefficient and toxic. This urges the need to development of new antitrypanosomal agents. We report the synthesis and biological profiling of 3'-deoxy-3'-fluororibonucleosides derived from 7-deazaadenine nucleosides bearing diverse substituents at position 7. They were synthesized through glycosylation of 6-chloro-7-bromo- or -7-iodo-7-deazapurine with protected 3'-fluororibose followed by cross-coupling reactions at position 7 and/or deprotection. Most of the title nucleosides displayed micromolar or submicromolar activity against Trypanosoma brucei brucei. The most active were the 7-bromo- and 7-iododerivatives which exerted double-digit nanomolar activity against T. b. brucei and T. b. gambiense and no cytotoxicity and thus represent promising candidates for further development.

• MeSH
• fibroblasty účinky léků   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• parazitické testy citlivosti MeSH
• ribonukleosidy chemická syntéza   farmakologie   toxicita   MeSH
• trypanocidální látky chemická syntéza   farmakologie   toxicita   MeSH
• Trypanosoma brucei brucei účinky léků   MeSH
• Trypanosoma brucei gambiense účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The compounds from eight different thiazolidine and thiazole series were assessed as potential antileishmanial scaffolds. They were tested for antileishmanial activity against promastigotes of Leishmania major using in vitro primary screen and dose response assays. The compounds from six thiazolidine and thiazole series were identified as the hits with antileishmanial activity against L. major. However, the analyses of structure-activity relations (SARs) showed that the interpretable SARs were obtained only for phenyl-indole hybrids (compounds C1, C2, C3 and C5) as the most effective compounds against L. major promastigotes (IC50 < 10 µM) with low toxicity to human fibroblasts. For the scaffold of these compounds, the most significant SAR patterns were: free N3 position of thiazolidinone core, absence of big fragments at the C5 position of thiazolidinone core and presence of halogen atoms or nitro group in the phenyl ring of phenyl-indole fragment. As previous studies showed that these compounds also have activity against the two Trypanosoma species, Trypanosoma brucei and Trypanosoma gambiense, their scaffold could be associated with a broader antiparasitic activity.

• MeSH
• fibroblasty účinky léků   MeSH
• knihovny malých molekul chemie   farmakologie   toxicita   MeSH
• Leishmania major účinky léků   MeSH
• lidé MeSH
• molekulární struktura MeSH
• parazitické testy citlivosti MeSH
• thiazolidiny chemie   farmakologie   toxicita   MeSH
• trypanocidální látky chemie   farmakologie   toxicita   MeSH
• Trypanosoma brucei brucei účinky léků   MeSH
• Trypanosoma brucei gambiense účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Rhomboid intramembrane proteases regulate pathophysiological processes, but their targeting in a disease context has never been achieved. We decoded the atypical substrate specificity of malaria rhomboid PfROM4, but found, unexpectedly, that it results from "steric exclusion": PfROM4 and canonical rhomboid proteases cannot cleave each other's substrates due to reciprocal juxtamembrane steric clashes. Instead, we engineered an optimal sequence that enhanced proteolysis >10-fold, and solved high-resolution structures to discover that boronates enhance inhibition >100-fold. A peptide boronate modeled on our "super-substrate" carrying one "steric-excluding" residue inhibited PfROM4 but not human rhomboid proteolysis. We further screened a library to discover an orthogonal alpha-ketoamide that potently inhibited PfROM4 but not human rhomboid proteolysis. Despite the membrane-immersed target and rapid invasion, ultrastructural analysis revealed that single-dosing blood-stage malaria cultures blocked host-cell invasion and cleared parasitemia. These observations establish a strategy for designing parasite-selective rhomboid inhibitors and expose a druggable dependence on rhomboid proteolysis in non-motile parasites.

• MeSH
• amidy chemická syntéza   chemie   farmakologie   MeSH
• antimalarika chemická syntéza   chemie   farmakologie   MeSH
• HEK293 buňky MeSH
• inhibitory proteas chemická syntéza   chemie   farmakologie   MeSH
• kyseliny boronové chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• malárie krev   farmakoterapie   metabolismus   MeSH
• molekulární struktura MeSH
• parazitické testy citlivosti MeSH
• peptidy chemická syntéza   chemie   farmakologie   MeSH
• Plasmodium falciparum účinky léků   metabolismus   MeSH
• proteasy krev   metabolismus   MeSH
• proteolýza účinky léků   MeSH
• protozoální proteiny antagonisté a inhibitory   krev   metabolismus   MeSH
• racionální návrh léčiv * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Targeting energy metabolism in Mycobacterium tuberculosis (Mtb) is a new paradigm in the search for innovative anti-TB drugs. NADH:menaquinone oxidoreductase is a non-proton translocating type II NADH dehydrogenase (NDH-2) that is an essential enzyme in the respiratory chain of Mtb and is not found in mammalian mitochondria. Phenothiazines (PTZs) represent one of the most known class of NDH-2 inhibitors, but their use as anti-TB drugs is currently limited by the wide range of potentially serious off-target effects. In this work, we designed and synthesized a series of new PTZs by decorating the scaffold in an unconventional way, introducing various halogen atoms. By replacing the sulfur atom with selenium, a dibromophenoselenazine 20 was also synthesized. Among the synthesized poly-halogenated PTZs (HPTZs), dibromo and tetrachloro derivatives 9 and 11, along with the phenoselenazine 20, emerged with a better anti-TB profile than the therapeutic thioridazine (TZ). They targeted non-replicating Mtb, were bactericidal, and synergized with rifampin and bedaquiline. Moreover, their anti-TB activity was found to be related to the NDH-2 inhibition. Most important, they showed a markedly reduced affinity to dopaminergic and serotonergic receptors respect to the TZ. From this work emerged, for the first time, as the poly-halogenation of the PTZ core, while permitting to maintain good anti-TB profile could conceivably lead to fewer CNS side-effects risk, making more tangible the use of PTZs for this alternative therapeutic application.

• MeSH
• antituberkulotika chemická syntéza   metabolismus   farmakologie   toxicita   MeSH
• Cercopithecus aethiops MeSH
• fenothiaziny chemická syntéza   metabolismus   farmakologie   toxicita   MeSH
• HEK293 buňky MeSH
• inhibitory enzymů chemická syntéza   metabolismus   farmakologie   toxicita   MeSH
• jaterní mikrozomy metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• Mycobacterium smegmatis účinky léků   MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• NADH-dehydrogenasa antagonisté a inhibitory   MeSH
• organoselenové sloučeniny chemická syntéza   metabolismus   farmakologie   toxicita   MeSH
• parazitické testy citlivosti MeSH
• receptory dopaminu D2 metabolismus   MeSH
• receptory serotoninové metabolismus   MeSH
• synergismus léků MeSH
• vazba proteinů MeSH
• Vero buňky MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Objectives Dermatophytosis, commonly known as ringworm, is a superficial fungal skin disease and zoonosis. Pythium oligandrum is a micromycete with mycoparasitic properties that is used in agriculture to control fungal infections on plants. Formulations containing P oligandrum were also developed for the treatment of dermatophytoses, but only a small number of case studies have been published. In order to document the process in simplified conditions in vitro, we investigated the effectiveness of P oligandrum against three pathogenic dermatophytes common in domestic animals. Methods Cultures of the pathogens grown on nutrient media and experimentally infected cat hair were treated with P oligandrum preparations in therapeutic concentration and the changes were documented by microscopic videos and scanning electron microscopy. Results There was strong mycoparasitic activity of P oligandrum against Microsporum canis, Microsporum gypseum and Trichophyton mentagrophytes. Conclusions and relevance P oligandrum was demonstrated to be effective against three common causes of dermatophytosis in vitro.

• MeSH
• antifungální látky farmakologie   MeSH
• kočky MeSH
• Microsporum účinky léků   MeSH
• nemoci koček farmakoterapie   mikrobiologie   MeSH
• parazitické testy citlivosti veterinární   MeSH
• Pythium * MeSH
• tinea farmakoterapie   mikrobiologie   veterinární   MeSH
• Trichophyton účinky léků   MeSH
• vlasy, chlupy mikrobiologie   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• kočky MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Current treatments for Human African Trypanosomiasis (HAT) are limited in their application, have undesirable dosing regimens and unsatisfactory toxicities highlighting the need for the development of a safer drug pipeline. Our medicinal chemistry programme in developing rapidly accessible and modifiable heterocyclic scaffolds led to the design and synthesis of novel substituted benzothiophenes, with 6-benzimidazol-1-ylbenzothiophene derivatives demonstrating significant antitrypanosomal activities (IC50 < 1 μM) against Trypanosoma brucei rhodesiense and no toxicity towards mammalian cells.

• MeSH
• antiprotozoální látky chemická syntéza   chemie   farmakologie   MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• parazitické testy citlivosti MeSH
• racionální návrh léčiv * MeSH
• thiofeny chemická syntéza   chemie   farmakologie   MeSH
• Trypanosoma brucei rhodesiense účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In our continuing search for biologically active natural product(s) of plant origin, Buddleja saligna, a South African medicinal plant, was screened in line with its traditional use for antidiabetic (yeast alpha glucosidase inhibitory) and antiplasmodial (against a chloroquine sensitive strain of Plasmodium falciparum (NF54)) activities. The hexane fraction showed the most promising activity with regards to its antidiabetic (IC(50) = 260 ± 0.112 µg/ml) and antiplasmodial (IC(50) = 8.5 ± 1.6 µg/ml) activities. Using activity guided fractionation three known terpenoids (betulonic acid, betulone and spinasterol) were isolated from this species for the first time. The compounds displayed varying levels of biological activities (antidiabetic: 27.31 µg/ml ≥ IC(50) ≥ 5.6 µg/ml; antiplasmodial: 14 µg/ml ≥ IC(50) ≥ 2 µg/ml) with very minimal toxicity.

• MeSH
• alfa-glukosidasy metabolismus   MeSH
• antimalarika chemie   izolace a purifikace   farmakologie   MeSH
• Buddleja chemie   MeSH
• inhibitory glykosidových hydrolas chemie   izolace a purifikace   farmakologie   MeSH
• kvasinky enzymologie   MeSH
• listy rostlin chemie   MeSH
• molekulární struktura MeSH
• parazitické testy citlivosti MeSH
• Plasmodium falciparum účinky léků   MeSH
• terpeny chemie   izolace a purifikace   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Acyclic nucleoside phosphonates (ANPs) are a promising class of antimalarial therapeutic drug leads that exhibit a wide variety of Ki values for Plasmodium falciparum (Pf) and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferases [HG(X)PRTs]. A novel series of ANPs, analogues of previously reported 2-(phosphonoethoxy)ethyl (PEE) and (R,S)-3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) derivatives, were designed and synthesized to evaluate their ability to act as inhibitors of these enzymes and to extend our ongoing antimalarial structure-activity relationship studies. In this series, (S)-3-hydroxy-2-(phosphonoethoxy)propyl (HPEP), (S)-2-(phosphonomethoxy)propanoic acid (CPME), or (S)-2-(phosphonoethoxy)propanoic acid (CPEE) are the acyclic moieties. Of this group, (S)-3-hydroxy-2-(phosphonoethoxy)propylguanine (HPEPG) exhibits the highest potency for PfHGXPRT, with a Ki value of 0.1 μM and a Ki value for human HGPRT of 0.6 μM. The crystal structures of HPEPG and HPEPHx (where Hx=hypoxanthine) in complex with human HGPRT were obtained, showing specific interactions with active site residues. Prodrugs for the HPEP and CPEE analogues were synthesized and tested for in vitro antimalarial activity. The lowest IC50 value (22 μM) in a chloroquine-resistant strain was observed for the bis-amidate prodrug of HPEPG.

• MeSH
• antimalarika chemická syntéza   chemie   farmakologie   MeSH
• hypoxanthinfosforibosyltransferasa antagonisté a inhibitory   metabolismus   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• nukleosidy chemická syntéza   chemie   farmakologie   MeSH
• organofosfonáty chemická syntéza   chemie   farmakologie   MeSH
• parazitické testy citlivosti MeSH
• Plasmodium falciparum účinky léků   enzymologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Protozoan parasites from the Plasmodiidae family are the causative agents of malaria. Inhibition of hypoxanthine-guanine-(xanthine) phosphoribosyltransferase (HG(X)PRT) has been suggested as a target for development of new anti-malarial therapeutics. Acyclic nucleoside phosphonates (ANPs) are potent and selective inhibitors of plasmodial HG(X)PRTs. A new series of ANPs, based on the chemical structure and inhibitory activity of three ANPs, 2-(phosphonoethoxy)ethyl with either guanine or hypoxanthine as the base (PEEG and PEEHx) and 3-hydroxy-2-(phosphonomethoxy)propyl with guanine as the base (HPMPG), were prepared. These compounds are stereoisomers of 3-fluoro-(2-phosphonoethoxy)propyl (FPEPs) and 3-fluoro-(2-phosphonomethoxy)propyl (FPMPs) analogues. Both the (R)- and (S)-isomers of these fluorinated derivatives have higher Ki values (by 10- to 1000-fold) for human HGPRT and Plasmodium falciparum HGXPRT than the non-fluorinated ANPs. Possible explanations for these changes in affinity are proposed based on docking studies using the known crystal structures of human HGPRT in complex with PEEG.

• MeSH
• antiprotozoální látky chemická syntéza   chemie   farmakologie   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• parazitické testy citlivosti MeSH
• pentosyltransferasy antagonisté a inhibitory   metabolismus   MeSH
• Plasmodium falciparum účinky léků   MeSH
• Plasmodium vivax účinky léků   MeSH
• puriny chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH