A5030445710- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Liver Disease and Transplantation
- Alzheimer's disease research and treatments
- Liver Disease Diagnosis and Treatment
- Trypanosoma species research and implications
- Research on Leishmaniasis Studies
- Health Systems, Economic Evaluations, Quality of Life
- Hemoglobinopathies and Related Disorders
- Medicinal Plants and Neuroprotection
- Blood groups and transfusion
- Malaria Research and Control
- Chemical synthesis and alkaloids
- Hematopoietic Stem Cell Transplantation
- Genital Health and Disease
- Synthesis and Biological Evaluation
- Organ Transplantation Techniques and Outcomes
- Cervical Cancer and HPV Research
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Sepsis Diagnosis and Treatment
- COVID-19 epidemiological studies
- Synthesis and biological activity
- Iron Metabolism and Disorders
- Hepatitis B Virus Studies
Grifols (Spain)
2021-2024
Health Economics and Outcomes Research (United Kingdom)
2023
Grifols (United States)
2020-2023
University of Dundee
2017-2021
Wellcome Centre for Anti-Infectives Research
2019-2021
Instituto Químico Biológico
2020
Universitat de Barcelona
2008-2020
Institut Municipal d'Assistència Sanitària
2016
Virginia Tech
2015
Universitat Autònoma de Barcelona
2008
Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and infantum, is one of major parasitic diseases worldwide. There an urgent need for new drugs to treat VL, because current therapies are unfit purpose in a resource-poor setting. Here, we describe development preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential this neglected tropical disease. The compound series was discovered repurposing hits from screen against related parasite...
A novel series of donepezil−tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites acetylcholinesterase (AChE) have been synthesized tested for their ability inhibit AChE, butyrylcholinesterase (BChE), AChE-induced Aβ aggregation. These compounds consist a unit tacrine or 6-chlorotacrine, which occupies same position as at AChE active site, 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety donepezil (or indane derivative thereof),...
We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer's disease. Biological screening performed in vitro and Escherichia coli cells has shown that these exhibit potent inhibitory activities against human acetylcholinesterase, butyrylcholinesterase, BACE-1, dual Aβ42 tau antiaggregating activity, brain permeability. Ex vivo studies with the leads (+)- (-)-7e slices C57bl6 mice revealed they efficiently protect Aβ-induced synaptic dysfunction,...
A family of huprine-tacrine heterodimers has been developed to simultaneously block the active and peripheral sites acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic molecular modeling studies, results in a highly potent inhibition catalytic activity human AChE and, more importantly, vitro neutralization pathological chaperoning effect toward aggregation both β-amyloid peptide (Aβ) prion with key role protein. Huprine-tacrine take on added value that they...
The combination of the scaffolds cholinesterase inhibitor huprine Y and antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) butyrylcholinesterase (BChE) that retain or improve properties capsaicin. Crystal structures their complexes AChE BChE revealed molecular basis for high potency. Brain penetration was confirmed by biodistribution studies C57BL6 mice, one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic...
Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, which are caused by the trypanosomatids Trypanosoma brucei, cruzi Leishmania species, among most deadly neglected tropical diseases. The development of drugs that active against several is appealing from a clinical economic viewpoint, seems feasible, as these parasites share metabolic pathways hence might be treatable common drugs. From benzonapthyridine 1, an inhibitor acetylcholinesterase (AChE) for we have found...
There is an urgent need for new treatments visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery GSK3494245/DDD01305143 (1) as preclinical candidate VL and, herein, we report medicinal chemistry program that led to its identification. A hit from phenotypic screen was optimized give compound with in vivo efficacy, hampered by poor solubility genotoxicity. The work original scaffold...
A new family of dual binding site acetylcholinesterase (AChE) inhibitors has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced self-induced β-amyloid (Aβ) aggregation β-secretase (BACE-1), cross the blood-brain barrier. The heterodimers consist a unit racemic or enantiopure huprine Y X donepezil-related 5,6-dimethoxy-2-[(4-piperidinyl)methyl]indane moiety as active peripheral mid-gorge-interacting moieties, respectively,...
Amyloid aggregation is linked to a large number of human disorders, from neurodegenerative diseases as Alzheimer's disease (AD) or spongiform encephalopathies non-neuropathic localized type II diabetes and cataracts. Because the formation insoluble inclusion bodies (IBs) during recombinant protein production in bacteria has been recently shown share mechanistic features with amyloid self-assembly, have emerged tool study aggregation. Herein we present fast, simple, inexpensive quantitative...
Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is most common cause of cardiac-related deaths in endemic regions Latin America. There an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects are only effective acute phase infection with limited efficacy chronic phase. Phenotypic high content screening against intracellular infected VERO cells was used to identify a novel hit series...
We describe the multigram synthesis and in vivo efficacy studies of a donepezil‒huprine hybrid that has been found to display promising vitro multitarget profile interest for treatment Alzheimer's disease (AD). Its features as key step novel preparative chromatographic resolution intermediate racemic huprine Y by chiral HPLC. Administration this compound transgenic CL4176 CL2006 Caenorhabditis elegans strains expressing human Aβ42, here used simplified animal models AD, led significant...
Transfusion of red blood cells (RBC) is an important component treatment for myelodysplastic syndromes (MDS). Patients receiving frequent transfusions are more likely to develop alloimmunization, immune reaction minor RBC antigens that increases the risk complications including delayed hemolysis. Phenotypic matching believed reduce alloimmunization although rigorous evidence lacking. This study examines association with clinical and economic outcomes may give insight into potential benefit...
Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-β (Aβ) peptide plays key role synaptic impairment and memory decline associated with neuronal dysfunction intra-neuronal accumulation of hyperphosphorylated tau protein. Two novel enantiopure rhein-huprine hybrids ((+)-1 (-)-1) exhibit potent inhibitory effects against human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), BACE-1 both Aβ antiaggregation activity vitro reduction on amyloid precursor...
A new nonavalent human papillomavirus (HPV) vaccine that includes genotypes 6/11/16/18/31/33/45/52/58 has been recently approved in Spain. previous study shown attributable fraction of HPV related diseases Spain is consistent with reported European and global studies. The aim the present was to estimate annual direct costs associated following HPV-related diseases: genital warts, high grade precancerous lesions cancer cervix, vulva, vagina, anus penis head neck cancer, caused by included...