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1.
Int J Mol Sci ; 25(5)2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38473953

RESUMO

Cryptosporidium parvum is an apicomplexan parasite causing persistent diarrhea in humans and animals. Issuing from target-based drug development, calcium-dependent protein kinase 1 inhibitors, collectively named bumped kinase inhibitors (BKIs), with excellent efficacies in vitro and in vivo have been generated. Some BKIs including BKI-1748 share a core structure with similarities to the first-generation antiprotozoal drug quinine, which is known to exert notorious side effects. Unlike quinine, BKI-1748 rapidly interfered with C. parvum proliferation in the human colon tumor (HCT) cell line HCT-8 cells and caused dramatic effects on the parasite ultrastructure. To identify putative BKI targets in C. parvum and in host cells, we performed differential affinity chromatography with cell-free extracts from non-infected and infected HCT-8 cells using BKI-1748 and quinine epoxy-activated sepharose columns followed by mass spectrometry. C. parvum proteins of interest were identified in eluates from columns coupled to BKI-1748, or in eluates from both BKI-1748 and quinine columns. However, no C. parvum proteins could be identified binding exclusively to BKI-1748. In contrast, 25 BKI-1748-specific binding proteins originating from HCT-8 cells were detected. Moreover, 29 C. parvum and 224 host cell proteins were identified in both BKI-1748 as well as in quinine eluates. In both C. parvum and host cells, the largest subset of binding proteins was involved in RNA binding and modification, with a focus on ribosomal proteins and proteins involved in RNA splicing. These findings extend previous results, showing that BKI-1748 interacts with putative targets involved in common, essential pathways such as translation and RNA processing.


Assuntos
Antineoplásicos , Antiprotozoários , Criptosporidiose , Cryptosporidium parvum , Cryptosporidium , Animais , Humanos , Quinina/farmacologia , Antiprotozoários/farmacologia , Antineoplásicos/farmacologia
2.
Bioorg Med Chem ; 102: 117679, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38461555

RESUMO

Trichomoniasis, a prevalent sexually transmitted infection (STI) caused by the protozoan Trichomonas vaginalis, has gained increased significance globally. Its relevance has grown in recent years due to its association with a heightened risk of acquiring and transmitting the human immunodeficiency virus (HIV) and other STIs. In addition, many publications have revealed a potential link between trichomoniasis and certain cancers. Metronidazole (MTZ), a nitroimidazole compound developed over 50 years ago, remains the first-choice drug for treatment. However, reports of genotoxicity and side effects underscore the necessity for new compounds to address this pressing global health concern. In this study, we synthesized ten pyrazole-nitroimidazoles 1(a-j) and 4-nitro-1-(hydroxyethyl)-1H-imidazole 2, an analog of metronidazole (MTZ), and assessed their trichomonacidal and cytotoxic effects. All compounds 1(a-j) and 2 exhibited IC50 values ≤ 20 µM and ≤ 41 µM, after 24 h and 48 h, respectively. Compounds 1d (IC50 5.3 µM), 1e (IC50 4.8 µM), and 1i (IC50 5.2 µM) exhibited potencies equivalent to MTZ (IC50 4.9 µM), the reference drug, after 24 h. Notably, compound 1i showed high anti-trichomonas activity after 24 h (IC50 5.2 µM) and 48 h (IC50 2.1 µM). Additionally, all compounds demonstrated either non-cytotoxic to HeLa cells (CC50 > 100 µM) or low cytotoxicity (CC50 between 69 and 100 µM). These findings suggest that pyrazole-nitroimidazole derivatives represent a promising heterocyclic system, serving as a potential lead for further optimization in trichomoniasis chemotherapy.


Assuntos
Antiprotozoários , Nitroimidazóis , Tricomoníase , Trichomonas vaginalis , Humanos , Nitroimidazóis/farmacologia , Metronidazol/farmacologia , Células HeLa , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Tricomoníase/tratamento farmacológico , Pirazóis/farmacologia , Pirazóis/uso terapêutico
3.
IUCrJ ; 11(Pt 2): 224-236, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38427455

RESUMO

Leishmaniasis is a neglected parasitic tropical disease with numerous clinical manifestations. One of the causative agents of cutaneous leishmaniasis (CL) is Leishmania tropica (L. tropica) known for causing ulcerative lesions on the skin. The adverse effects of the recommended available drugs, such as amphotericin B and pentavalent antimonial, and the emergence of drug resistance in parasites, mean the search for new safe and effective anti-leishmanial agents is crucial. Miltefosine (MIL) was the first recommended oral medication, but its use is now limited because of the rapid emergence of resistance. Pharmaceutical cocrystallization is an effective method to improve the physicochemical and biological properties of active pharmaceutical ingredients (APIs). Herein, we describe the cocrystallization of coumarin-3-carboxylic acid (CU, 1a; 2-oxobenzopyrane-3-carboxylic acid, C10H6O4) with five coformers [2-amino-3-bromopyridine (1b), 2-amino-5-(trifluoromethyl)-pyridine (1c), 2-amino-6-methylpyridine (1d), p-aminobenzoic acid (1e) and amitrole (1f)] in a 1:1 stoichiometric ratio via the neat grinding method. The cocrystals 2-6 obtained were characterized via single-crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis, as well as Fourier transform infrared spectroscopy. Non-covalent interactions, such as van der Waals, hydrogen bonding, C-H...π and π...π interactions contribute significantly towards the packing of a crystal structure and alter the physicochemical and biological activity of CU. In this research, newly synthesized cocrystals were evaluated for their anti-leishmanial activity against the MIL-resistant L. tropica and cytotoxicity against the 3T3 (normal fibroblast) cell line. Among the non-cytotoxic cocrystals synthesized (2-6), CU:1b (2, IC50 = 61.83 ± 0.59 µM), CU:1c (3, 125.7 ± 1.15 µM) and CU:1d (4, 48.71 ± 0.75 µM) appeared to be potent anti-leishmanial agents and showed several-fold more anti-leishmanial potential than the tested standard drug (MIL, IC50 = 169.55 ± 0.078 µM). The results indicate that cocrystals 2-4 are promising anti-leishmanial agents which require further exploration.


Assuntos
Antiprotozoários , Leishmania tropica , Leishmaniose Cutânea , Humanos , Antiprotozoários/farmacologia , Leishmaniose Cutânea/tratamento farmacológico , Cristalografia por Raios X , Cumarínicos/farmacologia
4.
Org Biomol Chem ; 22(9): 1812-1820, 2024 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-38328995

RESUMO

A library of hybrid molecules is developed based on the common chemical features shared by clemastine and tamoxifen both of which are well known for their antileishmanial activities. In the initial screening against Leishmania major and L. amazonensis promastigotes, as well as cytotoxicity assays using HepG2 cells, several hybrids showed submicromolar activity against the parasite and no toxicity against human cells. The compounds with an EC50 < 2 µM against promastigotes of both species and a selectivity index >10 were further characterized against intracellular amastigotes as well as promastigotes of species that cause both visceral and cutaneous leishmaniasis, such as L. infantum and L. braziliensis, respectively. These sequential screenings revealed the high pan-activity of this class of molecules against these species, with several compounds displaying an EC50 ≤ 2 µM against both promastigotes and intracellular amastigotes. Two of them were identified as the potential templates for lead optimization of this series having shown the highest activities against all species in both stages of parasite. The present findings can serve as a good starting point in the search for novel antileishmanial compounds that are easy to access and highly active.


Assuntos
Antiprotozoários , Leishmaniose Cutânea , Humanos , Animais , Camundongos , Clemastina/uso terapêutico , Macrófagos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Antiprotozoários/farmacologia , Células Hep G2 , Camundongos Endogâmicos BALB C
5.
Sci Rep ; 14(1): 3246, 2024 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-38332162

RESUMO

Leishmania donovani is the causal organism of leishmaniasis with critical health implications affecting about 12 million people around the globe. Due to less efficacy, adverse side effects, and resistance, the available therapeutic molecules fail to control leishmaniasis. The mitochondrial primase of Leishmania donovani (LdmtPRI1) is a vital cog in the DNA replication mechanism, as the enzyme initiates the replication of the mitochondrial genome of Leishmania donovani. Hence, we target this protein as a probable drug target against leishmaniasis. The de-novo approach enabled computational prediction of the three-dimensional structure of LdmtPRI1, and its active sites were identified. Ligands from commercially available drug compounds were selected and docked against LdmtPRI1. The compounds were chosen for pharmacokinetic study and molecular dynamics simulation based on their binding energies and protein interactions. The LdmtPRI1 gene was cloned, overexpressed, and purified, and a primase activity assay was performed. The selected compounds were verified experimentally by the parasite and primase inhibition assay. Capecitabine was observed to be effective against the promastigote form of Leishmania donovani, as well as inhibiting primase activity. This study's findings suggest capecitabine might be a potential anti-leishmanial drug candidate after adequate further studies.


Assuntos
Antiprotozoários , Leishmania donovani , Leishmaniose Visceral , Leishmaniose , Humanos , Leishmania donovani/genética , DNA Primase , DNA Mitocondrial , Capecitabina/uso terapêutico , Reposicionamento de Medicamentos , Leishmaniose/tratamento farmacológico , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Antiprotozoários/química
6.
PLoS Negl Trop Dis ; 18(2): e0012015, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38422164

RESUMO

BACKGROUND: Visceral leishmaniasis (VL) resolution depends on a wide range of factors, including the instauration of an effective treatment coupled to a functional host immune system. Patients with a depressed immune system, like the ones receiving methotrexate (MTX), are at higher risk of developing VL and refusing antileishmanial drugs. Moreover, the alarmingly growing levels of antimicrobial resistance, especially in endemic areas, contribute to the increasing the burden of this complex zoonotic disease. PRINCIPAL FINDINGS: To understand the potential links between immunosuppressants and antileishmanial drugs, we have studied the interaction of antimony (Sb) and MTX in a Leishmania infantum reference strain (LiWT) and in two L. infantum clinical strains (LiFS-A and LiFS-B) naturally circulating in non-treated VL dogs in Spain. The LiFS-A strain was isolated before Sb treatment in a case that responded positively to the treatment, while the LiFS-B strain was recovered from a dog before Sb treatment, with the dog later relapsing after the treatment. Our results show that, exposure to Sb or MTX leads to an increase in the production of reactive oxygen species (ROS) in LiWT which correlates with a sensitive phenotype against both drugs in promastigotes and intracellular amastigotes. LiFS-A was sensitive against Sb but resistant against MTX, displaying high levels of protection against ROS when exposed to MTX. LiFS-B was resistant to both drugs. Evaluation of the melting proteomes of the two LiFS, in the presence and absence of Sb and MTX, showed a differential enrichment of direct and indirect targets for both drugs, including common and unique pathways. CONCLUSION: Our results show the potential selection of Sb-MTX cross-resistant parasites in the field, pointing to the possibility to undermine antileishmanial treatment of those patients being treated with immunosuppressant drugs in Leishmania endemic areas.


Assuntos
Antiprotozoários , Leishmania infantum , Leishmaniose Visceral , Humanos , Animais , Cães , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Antimônio/farmacologia , Antimônio/uso terapêutico , Espécies Reativas de Oxigênio , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/veterinária , Resistência a Medicamentos
7.
Acta Trop ; 252: 107139, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38307362

RESUMO

Clotrimazole is an FDA approved drug and is widely used as an antifungal agent. An extensive body of research is available about its mechanism of action on various cell types but its mode of killing of Leishmania donovani parasites is unknown. L. donovani causes Visceral Leishmaniasis which is a public health problem with limited treatment options. Its present chemotherapy is expensive, has adverse effects and is plagued with drug resistance issues. In this study we have explored the possibility of repurposing clotrimazole as an antileishmanial drug. We have assessed its efficacy on the parasites and attempted to understand its mode of action. We found that it has a half-maximal inhibitory concentration (IC50) of 35.75 ± 1.06 µM, 12.75 ± 0.35 µM and 73 ± 1.41 µM in promastigotes, intracellular amastigotes and macrophages, respectively. Clotrimazole is 5.73 times more selective for the intracellular amastigotes as compared to the mammalian cell. Effect of clotrimazole was reduced by ergosterol supplementation. It leads to impaired parasite morphology. It alters plasma membrane permeability and disrupts plasma membrane potential. Mitochondrial function is compromised as is evident from increased ROS generation, depolarized mitochondrial membrane and decreased ATP levels. Cell cycle analysis of clotrimazole treated parasites shows arrest at sub-G0 phase suggesting apoptotic mode of cell death.


Assuntos
Antiprotozoários , Leishmania donovani , Leishmaniose Visceral , Animais , Clotrimazol/farmacologia , Clotrimazol/metabolismo , Clotrimazol/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Macrófagos , Pontos de Checagem do Ciclo Celular , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Mamíferos
8.
Acta Trop ; 252: 107155, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38373527

RESUMO

This study aimed to produce linalool loaded zinc oxide nanocomposite (LZNPs) and assess its in vitro and in vivo antileishmanial effects against Leishmania major. LZNPs was produced through the synthesis of an ethanolic solution containing polyvinyl alcohol. The average size of LZNPs was determined to be 105 nm. The findings indicated that LZNPs displayed significant (p < 0.01) antileishmanial effects on promastigotes and amastigotes. Following exposure of promastigotes to LZNPs, there was a notable rise in the percentage of early and late apoptotic cells from 9.0 to 57.2 %. The gene expression levels of iNOS, IFN-γ, and TNF-α in macrophages were upregulated in a dose-dependent approach following exposure to LZNPs. LZNPs alone and in conjunction with glucantime (Glu) resulted in a reduction in the diameter and parasite load of CL lesions in infected mice. Treatment of the CL-infected mice with LZNPs at 25 and 50 mg/kg mainly in combination with Glu-reduced the tissue level of malondialdehyde (MDA), increased both gene and protein expression of the antioxidant enzymes as well as raised the expression level of IFN-γ and IL-12 cytokines, whereas caused a significant reduction in the expression level of IL-4. The present study shows that LZNPs has potent antileishmanial effects and controls CL in a mice model through its antioxidant and immunomodulatory properties. Further investigation, especially in clinical trials, could explore the potential use of this nanocomposite in managing and treating CL.


Assuntos
Monoterpenos Acíclicos , Antiprotozoários , Cicloexanóis , Compostos de Tritil , Óxido de Zinco , Animais , Camundongos , Óxido de Zinco/farmacologia , Antioxidantes/farmacologia , Zinco , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Antimoniato de Meglumina , Camundongos Endogâmicos BALB C
9.
PLoS One ; 19(2): e0296728, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38354178

RESUMO

INTRODUCTION: American Tegumentary Leishmaniasis (ATL) treatment is based on pentavalent antimonials (Sb5+), but these drugs have been associated to several adverse effects. Hearing loss and tinnitus during treatment with meglumine antimoniate (MA) have already been reported. This study aimed to describe the usefulness of self-reporting of hearing loss and tinnitus in diagnosing MA-induced ototoxicity. METHODS: A prospective longitudinal study was conducted with 102 patients with parasitological diagnosis of ATL, treated with different MA schemes. The presence of clinical auditory toxicity was defined as the emergence or worsening of self-reporting hearing loss and/or tinnitus during monitoring. Measures of sensitivity, specificity, and the positive and negative predictive value of the patient's self-reporting of hearing loss and tinnitus in relation to the result of the audiometric test (considered the gold standard) were calculated. RESULTS: The age of the evaluated patients ranged from 15 to 81 years, with a median of 41 years, and most were male (73.5%). Seventy-five patients (73.5%) had cutaneous leishmaniasis and 27 (26.5%) mucosal leishmaniasis. Eighty-six patients (84.3%) received intramuscular (IM) treatment and 16 (15.7%) were treated with intralesional MA. During treatment, 18 (17,6%) had tinnitus and 7 (6,9%) had complaint of hearing loss. 53 (52%) patients had cochlear toxicity confirmed by tone threshold audiometry and high frequency audiometry, from which 60% received a dose of 20 mg Sb5+/kg/day (p = 0.015) and 96.2% were treated with IM MA (p = 0.001). Tinnitus has greater specificity and positive predictive value than hearing loss, with a low number of false positives, but with a high false negative value. CONCLUSION: Although the large number of false negatives suggests that self-report of hearing loss or tinnitus cannot be considered a good screening test for referring the patient to an audiometry, the low number of false positives suggests the need to value the patient's complaint for referral. Otherwise, this study reinforces the importance of audiological monitoring during treatment with MA, especially in those patients with self-reporting of hearing loss or tinnitus when treated with 20 mg Sb5+/kg/day via IM.


Assuntos
Antiprotozoários , Surdez , Perda Auditiva , Leishmaniose Cutânea , Compostos Organometálicos , Ototoxicidade , Zumbido , Humanos , Masculino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Antimoniato de Meglumina/efeitos adversos , Zumbido/induzido quimicamente , Zumbido/diagnóstico , Zumbido/tratamento farmacológico , Meglumina/efeitos adversos , Antiprotozoários/uso terapêutico , Estudos Longitudinais , Estudos Prospectivos , Compostos Organometálicos/efeitos adversos , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/tratamento farmacológico , Perda Auditiva/induzido quimicamente , Perda Auditiva/diagnóstico
10.
J Med Chem ; 67(4): 2849-2863, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38330051

RESUMO

Human African trypanosomiasis (HAT) still faces few therapeutic options and emerging drug resistance, stressing an urgency for novel antitrypanosomal drug discovery. Here, we describe lead optimization efforts aiming at improving antitrypanosomal efficacy and better physicochemical properties based on our previously reported optimized hit NPD-2975 (pIC50 7.2). Systematic modification of the 5-phenylpyrazolopyrimidinone NPD-2975 led to the discovery of a R4-substituted analogue 31c (NPD-3519), showing higher in vitro potency (pIC50 7.8) against Trypanosoma brucei and significantly better metabolic stability. Further, in vivo pharmacokinetic evaluation of 31c and experiments in an acute T. brucei mouse model confirmed improved oral bioavailability and antitrypanosomal efficacy at 50 mg/kg with no apparent toxicity. With good physicochemical properties, low toxicity, improved pharmacokinetic features, and in vivo efficacy, 31c may serve as a promising candidate for future drug development for HAT.


Assuntos
Antiprotozoários , Tripanossomicidas , Trypanosoma brucei brucei , Tripanossomíase Africana , Animais , Camundongos , Humanos , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Tripanossomíase Africana/tratamento farmacológico , Antiprotozoários/uso terapêutico , Desenvolvimento de Medicamentos
11.
Antimicrob Agents Chemother ; 68(3): e0112723, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38349159

RESUMO

The problems associated with the drugs currently used to treat leishmaniasis, including resistance, toxicity, and the high cost of some formulations, call for the urgent identification of new therapeutic agents with novel modes of action. The aggregated protein dye YAT2150 has been found to be a potent antileishmanial compound, with a half-maximal inhibitory concentration (IC50) of approximately 0.5 µM against promastigote and amastigote stages of Leishmania infantum. The encapsulation in liposomes of YAT2150 significantly improved its in vitro IC50 to 0.37 and 0.19 µM in promastigotes and amastigotes, respectively, and increased the half-maximal cytotoxic concentration in human umbilical vein endothelial cells to >50 µM. YAT2150 became strongly fluorescent when binding intracellular protein deposits in Leishmania cells. This fluorescence pattern aligns with the proposed mode of action of this drug in the malaria parasite Plasmodium falciparum, the inhibition of protein aggregation. In Leishmania major, YAT2150 rapidly reduced ATP levels, suggesting an alternative antileishmanial mechanism. To the best of our knowledge, this first-in-class compound is the only one described so far having significant activity against both Plasmodium and Leishmania, thus being a potential drug for the treatment of co-infections of both parasites.


Assuntos
Antiprotozoários , Leishmania infantum , Leishmaniose , Parasitos , Animais , Humanos , Células Endoteliais , Leishmaniose/tratamento farmacológico , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico
12.
Ticks Tick Borne Dis ; 15(3): 102315, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38301344

RESUMO

Canine babesiosis has been increasingly diagnosed in various regions of Germany such as north-eastern Germany in recent years. A dog with several relapses of Babesia canis infection after treatment with imidocarb is described. A 9-year-old male Magyar Viszla with B. canis infection was referred after two treatments with imidocarb (dosage 2.1 mg/kg SC) because of lethargy, fever and pancytopenia (additional treatments with prednisolone and doxycycline). Merozoites were detected in the blood smear and imidocarb treatment was repeated. Clinical signs, pancytopenia and a positive B. canis PCR occurred after the 3rd (6 mg/kg SC), 4th (7.7 mg/kg SC) and 5th (7.5 mg/kg SC and doxycycline for 4 weeks in addition) imidocarb injection and thorough tick prevention with isoxazoline and permethrin products. 12 days after the 5th injection, the PCR was negative for the first time. The dog was again presented with fever 35 days after the 5th injection. The B. canis PCR was positive and laboratory examination revealed pancytopenia. Treatment with atovaquone/azithromycin for 18 days was performed and no further relapse occurred for 32 weeks. In the case of suspected imidocarb resistance in B. canis infection, treatment with atovaquone/azithromycin can be an alternative.


Assuntos
Antiprotozoários , Babesia , Babesiose , Doenças do Cão , Pancitopenia , Masculino , Cães , Animais , Imidocarbo/uso terapêutico , Antiprotozoários/uso terapêutico , Atovaquona/farmacologia , Atovaquona/uso terapêutico , Doxiciclina/uso terapêutico , Azitromicina/uso terapêutico , Pancitopenia/tratamento farmacológico , Babesiose/tratamento farmacológico , Babesiose/epidemiologia , Babesiose/diagnóstico , Alemanha/epidemiologia , Falha de Tratamento , Doenças do Cão/tratamento farmacológico , Doenças do Cão/epidemiologia , Doenças do Cão/diagnóstico
13.
Sci Rep ; 14(1): 2482, 2024 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-38291076

RESUMO

Various drugs have been used for the treatment of leishmaniasis, but they often have adverse effects on the body's organs. In this study, we aimed to explore the effects of one type of drug, Miltefosine (MIL), and its analogue or modifier, liposomal Miltefosine (NMIL), on several fetal organs using both in silico analysis and practical tests on chicken embryos. Our in silico approach involved predicting the affinities of MIL and NMIL to critical proteins involved in leishmaniasis, including Vascular Endothelial Growth Factor A (VEGF-A), the Kinase insert domain receptor (KDR1), and apoptotic-regulator proteins (Bcl-2-associate). We then validated and supported these predictions through in vivo investigations, analyzing gene expression and pathological changes in angiogenesis and apoptotic mediators in MIL- and NMIL-treated chicken embryos. The results showed that NMIL had a more effective action towards VEGF-A and KDR1 in leishmaniasis, making it a better candidate for potential operative treatment during pregnancy than MIL alone. In vivo, studies also showed that chicken embryos under MIL treatment displayed less vascular mass and more degenerative and apoptotic changes than those treated with NMIL. These results suggest that NMIL could be a better treatment option for leishmaniasis during pregnancy.


Assuntos
Antiprotozoários , Leishmaniose Visceral , Embrião de Galinha , Animais , Leishmaniose Visceral/tratamento farmacológico , Antiprotozoários/farmacologia , Fator A de Crescimento do Endotélio Vascular/genética , Fosforilcolina
15.
Arch Med Res ; 55(2): 102958, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38290200

RESUMO

BACKGROUND: Chagas disease and cutaneous leishmaniasis, two parasitic diseases caused by Trypanosoma cruzi (T. cruzi) and Leishmania mexicana (L. mexicana), respectively, have a major global impact. Current pharmacological treatments for these diseases are limited and can cause severe side effects; thus, there is a need for new antiprotozoal drugs. METHODS: Using molecular docking, this work describes a structure-based virtual screening of an FDA-approved drug library against Trypanosoma cruzi and Leishmania mexicana glycolytic enzyme triosephosphate isomerase (TIM), which is highly conserved in these parasites. The selected compounds with potential dual inhibitory activity were tested in vitro to confirm their biological activity. RESULTS: The study showed that five compounds: nilotinib, chlorhexidine, protriptyline, cyproheptadine, and montelukast, were more active against T. cruzi, than the reference drugs, nifurtimox and benznidazole while chlorhexidine and protriptyline were the most active against L. mexicana. CONCLUSIONS: The analysis of these compounds and their structural characteristics may provide the basis for the development of new antiprotozoal agents.


Assuntos
Antiprotozoários , Doença de Chagas , Leishmaniose Cutânea , Trypanosoma cruzi , Humanos , Simulação de Acoplamento Molecular , Clorexidina/farmacologia , Clorexidina/uso terapêutico , Protriptilina/farmacologia , Protriptilina/uso terapêutico , Doença de Chagas/tratamento farmacológico , Leishmaniose Cutânea/tratamento farmacológico , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Antiprotozoários/química
16.
PLoS Negl Trop Dis ; 18(1): e0011559, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38166146

RESUMO

The parasite Leishmania donovani is one of the species causing visceral leishmaniasis in humans, a deadly infection claiming up to 40,000 lives each year. The current drugs for leishmaniasis treatment have severe drawbacks and there is an urgent need to find new anti-leishmanial compounds. However, the search for drug candidates is complicated by the intracellular lifestyle of Leishmania. Here, we investigate the use of human induced pluripotent stem cell (iPS)-derived macrophages (iMACs) as host cells for L. donovani. iMACs obtained through embryoid body differentiation were infected with L. donovani promastigotes, and high-content imaging techniques were used to optimize the iMACs seeding density and multiplicity of infection, allowing us to reach infection rates up to 70% five days after infection. IC50 values obtained for miltefosine and amphotericin B using the infected iMACs or mouse peritoneal macrophages as host cells were comparable and in agreement with the literature, showing the potential of iMACs as an infection model for drug screening.


Assuntos
Antiprotozoários , Células-Tronco Pluripotentes Induzidas , Leishmania donovani , Leishmaniose Visceral , Animais , Humanos , Camundongos , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Leishmaniose Visceral/parasitologia , Macrófagos/parasitologia
17.
Int J Mol Sci ; 25(2)2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38256271

RESUMO

Caffeic acid (CA) is one of the most abundant natural compounds present in plants and has a broad spectrum of beneficial pharmacological activities. However, in some cases, synthetic derivation of original molecules can expand their scope. This study focuses on the synthesis of caffeic acid phosphanium derivatives with the ambition of increasing their biological activities. Four caffeic acid phosphanium salts (CAPs) were synthesized and tested for their cytotoxic, antibacterial, antifungal, and amoebicidal activity in vitro, with the aim of identifying the best area for their medicinal use. CAPs exhibited significantly stronger cytotoxic activity against tested cell lines (HeLa, HCT116, MDA-MB-231 MCF-7, A2058, PANC-1, Jurkat) in comparison to caffeic acid. Focusing on Jurkat cells (human leukemic T cell lymphoma), the IC50 value of CAPs ranged from 0.9 to 8.5 µM while IC50 of CA was >300 µM. Antimicrobial testing also confirmed significantly higher activity of CAPs against selected microbes in comparison to CA, especially for Gram-positive bacteria (MIC 13-57 µM) and the yeast Candida albicans (MIC 13-57 µM). The anti-Acanthamoeba activity was studied against two pathogenic Acanthamoeba strains. In the case of A. lugdunensis, all CAPs revealed a stronger inhibitory effect (EC50 74-3125 µM) than CA (>105 µM), while in A. quina strain, the higher inhibition was observed for three derivatives (EC50 44-291 µM). The newly synthesized quaternary phosphanium salts of caffeic acid exhibited selective antitumor action and appeared to be promising antimicrobial agents for topical application, as well as potential molecules for further research.


Assuntos
Anti-Infecciosos , Antiprotozoários , Ácidos Cafeicos , Humanos , Sais , Anti-Infecciosos/farmacologia , Antiprotozoários/farmacologia , Células HeLa
18.
Pathog Glob Health ; 118(1): 40-46, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37183476

RESUMO

The visceral form of leishmaniasis (VL), due to infection by Leishmania infantum, is a neglected tropical disease. The accessible therapeutic options are limited. Artemisinin is an efficient antileishmanial product with poor biological availability that requires high repetition of therapeutic doses in VL. Solid lipid nanoparticles (SLNs) provide targeted delivery, increase bioavailability and reduce toxicity of the traditional therapeutic strategy. The spherical shape artemisinin-loaded SLNs were prepared in a particle diameter of 222.0 ± 14.0 nm. The SLNs showed no particular toxic effect on the parasites, whereas the native artemisinin demonstrated a significant toxicity rate of 31% in viability of the promastigotes at the 250 µg/ml concentration. The therapeutic efficacy of the artemisinin-loaded SLNs was demonstrated in the experimental VL, using the L. infantum-infected BALB/c mice, in the present study. The 10 and 20 mg/kg doses of artemisinin-loaded SLNs showed higher level of antileishmanial efficacy compared with the free artemisinin. There was a significant diminishing of the parasite burden in liver (84.7 ± 4.9%) and spleen (85.0 ± 3.1%) and hepatosplenomegaly by the artemisinin-loaded SLNs treated at 20 mg/kg compared to the free artemisinin. Therefore, the present study supports the superior efficacy of artemisinin-loaded SLNs over the free artemisinin and could be considered as a new therapeutic strategy in the treatment of leishmaniasis.


Assuntos
Antiprotozoários , Artemisininas , Leishmania infantum , Leishmaniose Visceral , Leishmaniose , Parasitos , Animais , Camundongos , Leishmaniose Visceral/tratamento farmacológico , Antiprotozoários/uso terapêutico , Leishmaniose/tratamento farmacológico , Artemisininas/uso terapêutico , Artemisininas/farmacologia , Camundongos Endogâmicos BALB C
19.
Drug Dev Res ; 85(1): e22126, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37915124

RESUMO

A hypoxic environment occurs predominantly in tumors. During the growth phase of a tumor, it grows until it exceeds its blood supply, leaving regions of the tumor in which the oxygen pressure is dramatically low. They are virtually absent in normal tissues, thus creating perfect conditions for selective bioreductive therapy of tumors. To this aim, a novel series of cytotoxic radiosensitizer agents were synthesized by linking the nitroimidazole scaffold with oxadiazole or triazole rings. The majority of the compounds exhibited moderate to excellent antiproliferative activities toward HCT116 cell line under normoxic and hypoxic conditions. The structure-activity relationship study revealed that compounds containing the free thiol group either in the oxadiazoles 11a,b or the triazoles 21a,b-23a,b demonstrated the strongest antiproliferative activity, which proves that the free thiol group plays a crucial role in the antiproliferative activity of our compounds under both normoxic (half-maximal inhibitory concentration [IC50 ] = 12.50-24.39 µM) and hypoxic conditions (IC50 = 4.69-11.56 µM). Radiosensitizing assay of the four most active cytotoxic compounds 11b and 21-23b assured the capability of the compounds to enhance the sensitivity of the tumor cells to the DNA damaging activity of γ-radiation (IC50 = 2.23-5.18 µM). To further investigate if the cytotoxicity of our most active compounds was due to a specific signaling pathway, the online software SwissTargetPrediction was exploited and a molecular docking study was done that proposed cyclin-dependent kinase 2 (CDK2) enzyme to be the most promising target. The CDK2 inhibitory assay assured this assumption as five out of six compounds demonstrated a comparable inhibitory activity with roscovitine, among which compound 21b showed threefold more potent inhibitory activity in comparison with the reference compound. A further biological evaluation proved compound 21b to have an apoptotic activity and cell cycle arrest activity at the G1 and S phases. During the AutoQSAR analysis, the model demonstrated excellent regression between the predicted and experimental activity with r2 = 0.86. Subsequently, we used the model to predict the activity of the test set compounds that came with r2 = 0.95.


Assuntos
Antineoplásicos , Antiprotozoários , Nitroimidazóis , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Linhagem Celular Tumoral , Hipóxia Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Citotoxinas , Nitroimidazóis/farmacologia , Antiprotozoários/farmacologia , Compostos de Sulfidrila , Inibidores de Proteínas Quinases/farmacologia
20.
Eur J Med Chem ; 264: 115946, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38043491

RESUMO

Pteridine reductase 1 (PTR1) is a catalytic protein belonging to the folate metabolic pathway in Trypanosmatidic parasites. PTR1 is a known target for the medicinal chemistry development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. In previous studies, new nitro derivatives were elaborated as PTR1 inhibitors. The compounds showing a diamino-pyrimidine core structure were previously developed but they showed limited efficacy. Therefore, a new class of phenyl-, heteroaryl- and benzyloxy-nitro derivatives based on the 2-nitroethyl-2,4,6-triaminopyrimidine scaffold were designed and tested. The compounds were assayed for their ability to inhibit T. brucei and L. major PTR1 enzymes and for their antiparasitic activity towards T. brucei and L. infantum parasites. To understand the structure-activity relationships of the compounds against TbPTR1, the X-ray crystallographic structure of the 2,4,6-triaminopyrimidine (TAP) was obtained and molecular modelling studies were performed. As a next step, only the most effective compounds against T. brucei were then tested against the amastigote cellular stage of T. cruzi, searching for a broad-spectrum antiprotozoal agent. An early ADME-Tox profile evaluation was performed. The early toxicity profile of this class of compounds was investigated by measuring their inhibition of hERG and five cytochrome P450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), cytotoxicity towards A549 cells and mitochondrial toxicity. Pharmacokinetic studies (SNAP-PK) were performed on selected compounds using hydroxypropyl-ß-cyclodextrins (50 % w/v) to preliminarily study their plasma concentration when administered per os at a dose of 20 mg/kg. Compound 1p, showed the best pharmacodynamic and pharmacokinetic properties, can be considered a good candidate for further bioavailability and efficacy studies.


Assuntos
Antiprotozoários , Doença de Chagas , Trypanosoma brucei brucei , Trypanosoma cruzi , Humanos , Relação Estrutura-Atividade , Antiprotozoários/química , Modelos Moleculares , Antiparasitários/farmacologia , Doença de Chagas/tratamento farmacológico
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