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1.
BMC Chem ; 15(1): 15, 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33673871

RESUMEN

BACKGROUND: Chemical and pharmacological investigations were performed on the stems of Cordia batesii (Boraginaeae); chemical studies included quantum calculations applied on a newly described compound. RESULTS: A new derivative of allantoin (1) named batesiin (2) was characterized. Thirteen other known compounds involving allantoin (1) were either isolated or identified. GC-MS enabled the identification of six compounds from a fraction containing essential oil. MeOH extract and some isolated compounds were tested in vitro against Pf7G8 CQS and Pf Dd2 CQR strains of Plasmodium falciparum; extract disclosed a moderate antiplasmodial activity (IC50 = 50 µg mL-1). Meantime, the CH2Cl2 extract and essential oil fraction were tested on a resistant mycobacterial strain of Mycobacterium tuberculosis; a potent antimycobacterial activity with a MIC = 9.52 µg mL-1 was deduced from essential oil. Density functional theory (DFT) calculations were carried on batesiin (2). Calculated chemical shifts at B3LYP/6-31G(d,p) and MPW1PW91/6-31G+(d,p) showed much better correlations with the experimental data. Time dependent DFT at B3LYP/6-31G+(d,p) displayed a major absorption band 3.01 nm higher than the experimental value. CONCLUSION: Cordia batesii can be considered as promising in search of compounds with antimalarial and antitubercular properties. DFT studies are very helpful when trying to learn more about the spectroscopic insights of a derivative of allantoin (1).

2.
PLoS One ; 16(1): e0246205, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33508016

RESUMEN

Light microscopy and rapid diagnostic tests are the two commonly used methods for malaria diagnosis that rely on the direct use of unprocessed blood samples. However, both methods do not have the level of sensitivity required for malaria diagnosis in cases of low density parasitaemia. We report here the diagnostic performance of a whole blood-based reverse transcription loop-mediated isothermal amplification method for Plasmodium falciparum malaria diagnosis in apparently healthy blood donors and febrile neonates in Cameroon. The presence of malaria parasites in whole blood samples was determined by light microscopy, antigen-based rapid diagnostic test (RDT), and by RT-LAMP using a "lyse and amplify" experimental protocol. Of the 256 blood donors tested, 36 (14.1%) were positive for malaria parasites by light microscopy, 38 (14.8%) were positive by RDT whereas 78 (30.5%) were positive by RT-LAMP. Only light microscopy and RT-LAMP detected infection among the febrile neonates (279 neonates, median age: 2 days, range: 1-9 days), with positivity rates of 8.6% and 12.2%, respectively. The overall concordance between the three methods were 75.9% for RT-LAMP and light microscopy, 75.1% for RT-LAMP and RDT, and 83.9% for light microscopy and RDT. Blood parasite densities were significantly lower in the neonates (mean: 97.6, range: 61-192 parasites/µL) compared to the blood donors (mean: 447.8, range: 63-11 000 parasites/µL). Together, the study demonstrates the usefulness of whole blood RT-LAMP for use in rapid pre-screening of blood donors and suspected neonates to avert severe consequences of P. falciparum infections.

3.
PLoS One ; 15(12): e0242510, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33382730

RESUMEN

The specific immune response to the Anopheles salivary peptide could be a pertinent and complementary tool to assess the risk of malaria transmission and the effectiveness of vector control strategies. This study aimed to obtain first reliable data on the current state of the Anopheles gSG6-P1 biomarker for assess the level of exposure to Anopheles bites in high malaria endemic areas in Cameroon. Blood smears were collected from people living in the neighborhoods of Youpwe (suburban area, continental) and Manoka (rural area, Island), both areas in the coastal region of Cameroon. Malaria infection was determined using thick blood smear microscopy, whereas the level of specific IgG response to gSG-P1 peptide was assessed by enzyme-linked immunosorbent assay from the dried blood spots. Of 266 (153 from Youpwe, 113 from Manoka) malaria endemic residents (mean age: 22.8±19.8 years, age range: 6 months-94 years, male/female sex ratio: 1/1.2, with Manoka mean age: 23.71±20.53, male/female sex ratio:1/1.13 and Youpwe mean age: 22.12±19.22, male/female sex ratio 1/0.67) randomly included in the study, Plasmodium infection prevalence was significantly higher in Manoka than in Youpwe (64.6% vs 12,4%, p = 0.0001). The anti-gSG6-P1 IgG response showed a high inter-individual heterogeneity and was significantly higher among individuals from Manoka than those from Youpwe (p = 0.023). Malaria infected individuals presented a higher anti-gSG6-P1 IgG antibody response than non-infected (p = 0.0004). No significant difference in the level of specific IgG response to gSG-P1 was observed according to long lasting insecticidal nets use. Taken together, the data revealed that human IgG antibody response to Anopheles gSG-P1 salivary peptide could be also used to assess human exposure to malaria vectors in Central African region. This finding strengthens the relevance of this candidate biomarker to be used for measuring human exposure to malaria vectors worldwide.


Asunto(s)
Anopheles/parasitología , Inmunoglobulina G/sangre , Proteínas de Insectos/inmunología , Malaria Falciparum/epidemiología , Mosquitos Vectores/parasitología , Plasmodium falciparum/inmunología , Proteínas y Péptidos Salivales/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Camerún/epidemiología , Niño , Preescolar , Pruebas con Sangre Seca , Enfermedades Endémicas , Femenino , Humanos , Inmunoglobulina G/biosíntesis , Lactante , Proteínas de Insectos/sangre , Malaria Falciparum/diagnóstico , Malaria Falciparum/inmunología , Malaria Falciparum/parasitología , Masculino , Persona de Mediana Edad , Prevalencia , Población Rural , Proteínas y Péptidos Salivales/sangre , Población Urbana
4.
Sci Rep ; 10(1): 17932, 2020 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-33087791

RESUMEN

Molecular hybridization of privileged scaffolds may generate novel antiplasmodial chemotypes that display superior biological activity and delay drug resistance. In the present study, we describe the in vitro activities and mode of action of 3',4'-dihydro-2'H-spiro[indoline-3,1'-isoquinolin]-2-ones, a novel class of spirofused tetrahydroisoquinoline-oxindole hybrids, as novel antimalarial agents. Whole cell phenotypic screening of these compounds identified (14b), subsequently named (±)-moxiquindole, as the most potent compound in the current series with equipotent antiplasmodial activity against both chloroquine sensitive and multidrug resistant parasite strains with good selectivity. The compound was active against all asexual stages of the parasite including inhibition of merozoite egress. Additionally, (±)-moxiquindole exhibited significant inhibitory effects on hemoglobin degradation, and disrupted vacuolar lipid dynamics. Taken together, our data confirm the antiplasmodial activity of (±)-moxiquindole, and identify 3'4'-dihydro-2'H-spiro[indoline-3,1'-isoquinolin]-2-ones as a novel class of antimalarial agents with multiple modes of action.

5.
J Trop Med ; 2020: 1843780, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32518565

RESUMEN

Malaria is a leading cause of morbidity and mortality in Africa. Children are mostly exposed to this disease; numerous studies have investigated the relationship between child malnutrition and either malaria morbidity or infection. Few studies demonstrated the interaction between child malnutrition and specific anti-Plasmodium falciparum immune responses. The purpose of this study was to investigate the impact of nutritional status and iron on total anti-Plasmodium falciparum IgG levels in children living in the Gado-Badzéré refugee camp. We carried out a cross-sectional study during August-November 2017 in the Gado-Badzéré refugee camp in the East region of Cameroon. Children aged from 6 to 59 months with fever were recruited from the medical center. The data were recorded using a standardized data collection sheet and were analyzed using SPSS and WHO Anthro software. The total anti-Pf 3D7 total IgG level was determined using an ELISA technique while a colorimetric method was used to measure the total iron level. A total of 83 patients aged 6-59 months were enrolled in this study. The prevalence of malaria and malnutrition was 47% and 31%, respectively. Acute malnutrition was statistically less recurrent in noninfected children compared with that in the infected children. The infection tended to have significant influence on the level of anti-Plasmodium falciparum antibodies in children. In addition, nutritional status and serum iron levels had no significant influence on children's anti-Pf IgG T levels. Malaria and malnutrition remain real public health problems in the Gado-badzéré refugee camp. Knowledge of the nutritional profile of the population would be of great benefit in setting up an appropriate health program. We therefore suggest that more standardized studies be conducted to highlight the effect of nutrition and micronutrients on immunological status.

6.
BMJ Open ; 10(3): e031075, 2020 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-32193257

RESUMEN

INTRODUCTION: Hepatitis B virus (HBV) is a bloodborne virus which can be transmitted via percutaneous and mucocutaneous exposure to infected body fluid. Healthcare workers (HCWs) who are continuously exposed to different body fluids are at an increased risk of contracting and transmitting this virus. It is thus important to evaluate the knowledge and attitude of HCWs towards HBV and the prevalence of HBV infection among them. METHODS: This cross-sectional study was carried out between April and September 2017. Overall, 398 HCWs were recruited for this study. Knowledge on the route of HBV transmission and attitude towards HBV were evaluated using a well-structured questionnaire. Hepatitis B surface antigen (HBsAg) positivity was obtained using the Monolisa HBsAg ULTRA kit (Bio-Rad). Data were analysed using SPSS V.20. RESULTS: Among the HCWs who participated in this study, 338 (84.9%) had heard of HBV, and 269 (67.6%) of them had adequate knowledge on the route of HBV transmission. Medical doctors were the most knowledgeable among biomedical workers and students (76.5%). The rate of stigma was highest among nurses (87, 38.8%). The prevalence of HBsAg positivity was high (42, 10.6%) given that there is an efficient and available vaccine. Overall, over 70% of HCWs invited to participate in this study responded. CONCLUSION: Knowledge on the route of HBV transmission was fair, and the level of stigmatisation of HBV-infected patients and the prevalence of HBV infection were high in this study. A sensitisation campaign should be carried out to educate HCWs on HBV, thus reducing the level of stigma associated with HBV as well as the probability of contracting HBV as a nosocomial infection.

7.
PLoS Pathog ; 16(1): e1008261, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31999807

RESUMEN

Disruption of blood-brain barrier (BBB) function is a key feature of cerebral malaria. Increased barrier permeability occurs due to disassembly of tight and adherens junctions between endothelial cells, yet the mechanisms governing junction disassembly and vascular permeability during cerebral malaria remain poorly characterized. We found that EphA2 is a principal receptor tyrosine kinase mediating BBB breakdown during Plasmodium infection. Upregulated on brain microvascular endothelial cells in response to inflammatory cytokines, EphA2 is required for the loss of junction proteins on mouse and human brain microvascular endothelial cells. Furthermore, EphA2 is necessary for CD8+ T cell brain infiltration and subsequent BBB breakdown in a mouse model of cerebral malaria. Blocking EphA2 protects against BBB breakdown highlighting EphA2 as a potential therapeutic target for cerebral malaria.


Asunto(s)
Barrera Hematoencefálica/parasitología , Malaria Cerebral/parasitología , Receptor EphA2/metabolismo , Adolescente , Animales , Barrera Hematoencefálica/metabolismo , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Malaria Cerebral/genética , Malaria Cerebral/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Plasmodium falciparum/fisiología , Receptor EphA2/genética
8.
Malar J ; 18(1): 337, 2019 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-31581943

RESUMEN

BACKGROUND: The recent emergence in Southeast Asia of artemisinin resistance poses major threats to malaria control and elimination globally. Green nanotechnologies can constitute interesting tools for discovering anti-malarial medicines. This systematic review focused on the green synthesis of metal nanoparticles as potential source of new antiplasmodial drugs. METHODS: Seven electronic database were used following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 17 papers were included in the systematic review. 82.4% of the studies used plant leaves to produce nanoparticles (NPs) while three studies used microorganisms, including bacteria and fungi. Silver was the main metal precursor for the synthesis of NPs. The majority of studies obtained nanoparticles spherical in shape, with sizes ranging between 4 and 65 nm, and reported no or little cytotoxic effect of the NPs. Results based on 50% inhibitory concentration (IC50) varied between studies but, in general, could be divided into three NP categories; (i) those more effective than positive controls, (ii) those more effective than corresponding plant extracts and, (iii) those less effective than the positive controls or plant extracts. CONCLUSIONS: This study highlights the high antiplasmodial potential of green-synthesized metal nanoparticles thereby underscoring the possibility to find and develop new anti-malarial drugs based on green synthesis approaches. However, the review also highlights the need for extensive in vitro and in vivo studies to confirm their safety in humans and the elucidation of the mechanism of action.


Asunto(s)
Antimaláricos/síntesis química , Descubrimiento de Drogas/tendencias , Nanopartículas del Metal/química , Hojas de la Planta/metabolismo , Plasmodium falciparum/efectos de los fármacos , Artemisininas/farmacología , Malaria/tratamiento farmacológico , Extractos Vegetales/química , Plata
9.
PLoS One ; 14(9): e0221895, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31479501

RESUMEN

The emergence of artemisinin-resistant parasites since the late 2000s at the border of Cambodia and Thailand poses serious threats to malaria control globally, particularly in Africa which bears the highest malaria transmission burden. This study aimed to obtain reliable data on the current state of the kelch13 molecular marker for artemisinin resistance in Plasmodium falciparum in Cameroon. DNA was extracted from the dried blood spots collected from epidemiologically distinct endemic areas in the Center, Littoral and North regions of Cameroon. Nested PCR products from the Kelch13-propeller gene were sequenced and analyzed on an ABI 3730XL automatic sequencer. Of 219 dried blood spots, 175 were sequenced successfully. We identified six K13 mutations in 2.9% (5/175) of samples, including 2 non-synonymous, the V589I allele had been reported in Africa already and one new allele E612K had not been reported yet. These two non-synonymous mutations were uniquely found in parasites from the Littoral region. One sample showed two synonymous mutations within the kelch13 gene. We also observed two infected samples with mixed K13 mutant and K13 wild-type infection. Taken together, our data suggested the circulation of the non-synonymous K13 mutations in Cameroon. Albeit no mutations known to be associated with parasite clearance delays in the study population, there is need for continuous surveillance for earlier detection of resistance as long as ACTs are used and scaled up in the community.


Asunto(s)
Malaria Falciparum/parasitología , Plasmodium falciparum/genética , Proteínas Protozoarias/genética , Alelos , Antimaláricos/farmacología , Artemisininas/farmacología , Camerún/epidemiología , Niño , Preescolar , Resistencia a Medicamentos/genética , Femenino , Genes Protozoarios , Humanos , Secuencia Kelch , Malaria Falciparum/epidemiología , Masculino , Mutación , Plasmodium falciparum/efectos de los fármacos , Polimorfismo Genético , Estudios Prospectivos
10.
Methods Mol Biol ; 2013: 29-44, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31267491

RESUMEN

Malaria infection is one of the major causes of deaths in the African continent. The high burden of malaria in Africa is due to P. falciparum, which adapts and cospecializes with Anopheles gambiae, the most effective and widespread malaria vector. Since 2000, the incidence of malaria has been reduced by 17% and malaria mortality rates by 26%. However, the rate of decline has stalled and even reversed in some regions since 2014. In 2017 as described by the latest World malaria report, 219 million malaria cases were reported, up from 2017 million cases reported in 2016 in 91 countries, and the global tally of malaria deaths reached 435,000 deaths, compared with 451,000 estimated deaths in 2016. Despite these achievements, the African region continues to account for about 92% of malaria cases and deaths worldwide. Therefore, it is important to master the current situation of malaria in Africa to see how to better plan its elimination. In this chapter, we present the current situation and prospective means to improve it, including a salutogenesis approach.


Asunto(s)
Malaria/epidemiología , Malaria/prevención & control , África/epidemiología , Animales , Anopheles/parasitología , Humanos , Mosquitos Vectores/parasitología
11.
Methods Mol Biol ; 2013: 73-82, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31267494

RESUMEN

Diagnosing malaria is a key component of effective case management and monitoring of antimalarial programs worldwide. This chapter features the different diagnostic approaches currently in use or under testing for use in case management and/or epidemiological studies of malaria. Emphasis is laid on the basic principles of each diagnostic approach as well as their operational limits under different malaria endemicity settings. The discussed methods are defined as "conventional" or "unconventional" depending on their widespread use in malaria case management. The chapter therefore provides a practical guide to students, health practitioners, and field researchers involved in the fight against malaria through community-based interventions.


Asunto(s)
Malaria/diagnóstico , Antimaláricos , Humanos , Malaria/prevención & control
12.
PLoS One ; 14(4): e0216133, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31022294

RESUMEN

Presence of mature gametocyte forms of malaria parasites in peripheral blood is a key requirement for malaria transmission. Yet, studies conducted in most malaria transmission zones report the absence of gametocyte in the majority of patients. We therefore sought to determine the risk factors of both all-stage and mature gametocyte carriage in an area with high stable transmission of Plasmodium falciparum in Cameroon. Gametocyte positivity was determined using three complementary methods: thick blood smear microscopy, RT-PCR and RT-LAMP, whereas exposure to the infection was assessed by enzyme-linked immunosorbent assay. Of 361 malaria endemic residents randomly included in the study (mean age: 28±23 years, age range: 2-100 years, male/female sex ratio: 1.1), 87.8% were diagnosed with P. falciparum infection, of whom 45.7% presented with fever (axillary body temperature ≥37.5°C). Mature gametocyte positivity was 1.9% by thick blood smear microscopy and 8.9% by RT-PCR targeting the mature gametocyte transcript, Pfs25. The gametocyte positivity rate was 24.1% and 36.3% by RT-PCR or RT-LAMP, respectively, when targeting the sexual stage marker, Pfs16. Multivariate analyses revealed anemia as a common independent risk factor for both mature and all-stage gametocyte carriage, whereas fever and low anti-gametocyte antibody levels were independently associated with all-stage gametocyte carriage only. Taken together, the data suggest important differences in risk factors of gametocyte carriage depending on stage analyzed, with anemia, fever and low antiplasmodial plasma antibody levels representing the major contributing risk factors.


Asunto(s)
Portador Sano/transmisión , Demografía , Células Germinativas/fisiología , Malaria Falciparum/sangre , Malaria Falciparum/transmisión , Plasmodium falciparum/fisiología , Adolescente , Adulto , Camerún/epidemiología , Femenino , Humanos , Malaria Falciparum/epidemiología , Malaria Falciparum/inmunología , Masculino , Análisis Multivariante , Prevalencia , Factores de Riesgo , Adulto Joven
13.
Int J Parasitol Drugs Drug Resist ; 7(1): 120-129, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28285258

RESUMEN

Drugs against malaria are losing their effectiveness because of emerging drug resistance. This underscores the need for novel therapeutic options for malaria with mechanism of actions distinct from current antimalarials. To identify novel pharmacophores against malaria we have screened compounds containing structural features of natural products that are pharmacologically relevant. This screening has identified a 4-nitro styrylquinoline (SQ) compound with submicromolar antiplasmodial activity and excellent selectivity. SQ exhibits a cellular action distinct from current antimalarials, acting early on malaria parasite's intraerythrocytic life cycle including merozoite invasion. The compound is a fast-acting parasitocidal agent and also exhibits curative property in the rodent malaria model when administered orally. In this report, we describe the synthesis, preliminary structure-function analysis, and the parasite developmental stage specific action of the SQ scaffold.


Asunto(s)
Aminoquinolinas/farmacología , Antimaláricos/farmacología , Descubrimiento de Drogas , Plasmodium falciparum/efectos de los fármacos , Estirenos/farmacología , Administración Oral , Aminoquinolinas/química , Aminoquinolinas/uso terapéutico , Animales , Antimaláricos/química , Antimaláricos/uso terapéutico , Eritrocitos/parasitología , Estadios del Ciclo de Vida/efectos de los fármacos , Malaria/tratamiento farmacológico , Malaria/parasitología , Merozoítos/efectos de los fármacos , Pruebas de Sensibilidad Parasitaria , Plasmodium berghei , Plasmodium falciparum/crecimiento & desarrollo , Ratas , Estirenos/química , Estirenos/uso terapéutico
14.
Biomark Res ; 4: 25, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27999673

RESUMEN

There is an urgent need for new anti-malaria drugs with broad therapeutic potential and novel mode of action, for effective treatment and to overcome emerging drug resistance. Plant-derived anti-malarials remain a significant source of bioactive molecules in this regard. The multicomponent formulation forms the basis of phytotherapy. Mechanistic reasons for the poly-pharmacological effects of plants constitute increased bioavailability, interference with cellular transport processes, activation of pro-drugs/deactivation of active compounds to inactive metabolites and action of synergistic partners at different points of the same signaling cascade. These effects are known as the multi-target concept. However, due to the intrinsic complexity of natural products-based drug discovery, there is need to rethink the approaches toward understanding their therapeutic effect. This review discusses the multi-target phytotherapeutic concept and its application in biomarker identification using the modified reverse pharmacology - systems biology approach. Considerations include the generation of a product library, high throughput screening (HTS) techniques for efficacy and interaction assessment, High Performance Liquid Chromatography (HPLC)-based anti-malarial profiling and animal pharmacology. This approach is an integrated interdisciplinary implementation of tailored technology platforms coupled to miniaturized biological assays, to track and characterize the multi-target bioactive components of botanicals as well as identify potential biomarkers. While preserving biodiversity, this will serve as a primary step towards the development of standardized phytomedicines, as well as facilitate lead discovery for chemical prioritization and downstream clinical development.

15.
PLoS One ; 11(11): e0165506, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27824866

RESUMEN

Highly sensitive and field deployable molecular diagnostic tools are critically needed for detecting submicroscopic, yet transmissible levels of malaria parasites prevalent in malaria endemic countries worldwide. A reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay was developed and evaluated in comparison with thick blood smear microscopy, an antigen-based rapid diagnostic test (RDT), and an in-house RT-PCR targeting the same RT-LAMP transcript. The optimized assay detected Plasmodium falciparum infections in as little as 0.25ng of total parasite RNA, and exhibited a detection limit of 0.08 parasites/ µL when tested directly on infected whole blood lysates, or ~0.0008 parasites/ µL when using RNA extracts. Assay positivity was observed as early as eight minutes from initiation of the RT-LAMP and in most cases the reaction was complete before twenty minutes. Clinical evaluation of the assay on 132 suspected malaria cases resulted in a positivity rate of 90% for RT-LAMP using extracted RNA, and 85% when using whole blood lysates. The positivity rates were 70% for P. falciparum-specific RDT, 83% for RT-PCR, and 74% for thick blood smear microscopy (Mean parasite density = 36,986 parasites/ µL). Concordance rates between the developed RT-LAMP and comparator tests were greater than 75%, the lowest being with light microscopy (78%, McNemar's test: P = 0.0002), and the highest was with RT-PCR (87%, McNemar's test: P = 0.0523). Compared to reference RT-PCR, assay sensitivity was 90% for RT-LAMP on whole blood, and 96% for RT-LAMP using corresponding RNA extracts. Electricity-free heaters were further developed and evaluated in comparison with a battery-operated isothermal amplification machine for use with the developed test in resource-limited settings. Taken together, the data highlight the benefits of targeting high abundant RNA transcripts in molecular diagnosis, as well as the potential usefulness of the developed RT-LAMP-assay in malaria diagnosis in low to high parasite density settings.


Asunto(s)
Malaria Falciparum/diagnóstico , Malaria Falciparum/parasitología , Técnicas de Diagnóstico Molecular/métodos , Plasmodium falciparum/genética , Secuencia de Bases , Humanos , Límite de Detección , Técnicas de Amplificación de Ácido Nucleico/métodos , Transcripción Reversa , Sensibilidad y Especificidad , Alineación de Secuencia
16.
PLoS Pathog ; 12(7): e1005763, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27467575

RESUMEN

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.


Asunto(s)
Antimaláricos/uso terapéutico , Conjuntos de Datos como Asunto , Descubrimiento de Drogas/métodos , Malaria/tratamiento farmacológico , Enfermedades Desatendidas/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Humanos , Bibliotecas de Moléculas Pequeñas
17.
Int J Parasitol Drugs Drug Resist ; 6(1): 85-92, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27054067

RESUMEN

We screened a collection of synthetic compounds consisting of natural-product-like substructural motifs to identify a spirocyclic chromane as a novel antiplasmodial pharmacophore using an unbiased cell-based assay. The most active spirocyclic compound UCF 201 exhibits a 50% effective concentration (EC50) of 350 nM against the chloroquine-resistant Dd2 strain and a selectivity over 50 using human liver HepG2 cells. Our analyses of physicochemical properties of UCF 201 showed that it is in compliance with Lipinski's parameters and has an acceptable physicochemical profile. We have performed a limited structure-activity-relationship study with commercially available chromanes preserving the spirocyclic motif. Our evaluation of stage specificities of UCF 201 indicated that the compound is early-acting in blocking parasite development at ring, trophozoite and schizont stages of development as well as merozoite invasion. SPC is an attractive lead candidate scaffold because of its ability to act on all stages of parasite's aexual life cycle unlike current antimalarials.


Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Benzofuranos/farmacología , Eritrocitos/parasitología , Malaria/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Compuestos de Espiro/farmacología , Animales , Antimaláricos/síntesis química , Antimaláricos/aislamiento & purificación , Benzofuranos/uso terapéutico , Evaluación Preclínica de Medicamentos , Estadios del Ciclo de Vida/efectos de los fármacos , Malaria/parasitología , Merozoítos/efectos de los fármacos , Merozoítos/crecimiento & desarrollo , Ratones Endogámicos BALB C , Plasmodium berghei , Plasmodium falciparum/crecimiento & desarrollo , Esquizontes/efectos de los fármacos , Esquizontes/crecimiento & desarrollo , Compuestos de Espiro/uso terapéutico , Relación Estructura-Actividad , Trofozoítos/efectos de los fármacos , Trofozoítos/crecimiento & desarrollo
18.
Malar J ; 13: 456, 2014 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-25421605

RESUMEN

BACKGROUND: The emerging resistance of Plasmodium species to currently available anti-malarials remains a public health concern, hence the need for new effective, safe and affordable drugs. Natural products remain a reliable source of drugs. Nefang is a polyherbal anti-malarial of the Cameroonian folklore medicine with demonstrated in vitro antiplasmodial and antioxidant activities. It is composed of Mangifera indica (bark and leaf), Psidium guajava, Carica papaya, Cymbopogon citratus, Citrus sinensis, Ocimum gratissimum (leaves). This study aimed at investigating the suppressive, prophylactic and curative activities of Nefang in Plasmodium infected rodent models. METHODS: Systemic acute oral toxicity of Nefang aqueous and ethanol extracts was assessed in mice up to a dose of 5,000 mgkg(-1) body weight. BALB/c mice and Wistar rats were inoculated with Plasmodium chabaudi chabaudi and Plasmodium berghei, respectively, and treated with Nefang, the Mangifera indica bark/Psidium guajava combination and a Psidium guajava leaf aqueous extracts (75, 150, 300 and 600 mgkg(-1) bwt). Their schizonticidal activity was then evaluated using the Peter's 4-day suppressive test). The prophylactic and curative (Rane's Test) activity of Nefang was also evaluated by determining the parasitaemia, survival time, body weight and temperature in pre-treated rodents. RESULTS: Acute oral toxicity of the extract did not cause any observed adverse effects. Percent suppressions of parasitaemia at 600 mgkg(-1) bwt were as follows (P. berghei/P. chabaudi): Nefang - 82.9/86.3, Mangifera indica bark/Psidium guajava leaf combination extract - 79.5/81.2 and Psidium guajava leaf - 58.9/67.4. Nefang exhibited a prophylactic activity of 79.5% and its chemotherapeutic effects ranged from 61.2 - 86.1% with maximum effect observed at the highest experimental dose. CONCLUSION: These results indicate that Nefang has excellent in vivo anti-malarial activities against P. berghei and P. chabaudi, upholding earlier in vitro antiplasmodial activities against multi-drug resistant P. falciparum parasites as well as its traditional use. Hence, Nefang represents a promising source of new anti-malarial agents.


Asunto(s)
Antimaláricos/administración & dosificación , Productos Biológicos/administración & dosificación , Medicina de Hierbas , Malaria/tratamiento farmacológico , Malaria/prevención & control , Animales , Sangre/parasitología , Peso Corporal , Quimioprevención/métodos , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Parasitemia/tratamiento farmacológico , Parasitemia/prevención & control , Ratas Wistar , Análisis de Supervivencia , Temperatura , Resultado del Tratamiento
19.
J Med Chem ; 57(17): 7425-34, 2014 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-25137549

RESUMEN

New antimalarial agents that exhibit multistage activities against drug-resistant strains of malaria parasites represent good starting points for developing next-generation antimalarial therapies. To facilitate the progression of such agents into the development phase, we developed an image-based parasitological screening method for defining drug effects on different asexual life cycle stages of Plasmodium falciparum. High-throughput screening of a newly assembled diversity-oriented synthetic library using this approach led to the identification of carbohybrid-based 2-aminopyrimidine compounds with fast-acting growth inhibitory activities against three laboratory strains of multidrug-resistant P. falciparum. Our structure-activity relationship study led to the identification of two derivatives (8aA and 11aA) as the most promising antimalarial candidates (mean EC50 of 0.130 and 0.096 µM against all three P. falciparum strains, selectivity indices >600, microsomal stabilities >80%, and mouse malaria ED50 values of 0.32 and 0.12 mg/kg/day, respectively), targeting all major blood stages of multidrug-resistant P. falciparum parasites.


Asunto(s)
Antimaláricos/farmacología , Estadios del Ciclo de Vida/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Pirimidinas/farmacología , Animales , Antimaláricos/química , Antimaláricos/farmacocinética , Área Bajo la Curva , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Células Hep G2 , Interacciones Huésped-Parásitos/efectos de los fármacos , Humanos , Malaria/parasitología , Malaria/prevención & control , Masculino , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos BALB C , Modelos Químicos , Estructura Molecular , Plasmodium chabaudi/efectos de los fármacos , Plasmodium chabaudi/fisiología , Plasmodium falciparum/crecimiento & desarrollo , Pirimidinas/química , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
20.
Biomed Res Int ; 2014: 835013, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24877138

RESUMEN

Nefang, a polyherbal product composed of Mangifera indica (bark and leaf), Psidium guajava, Carica papaya, Cymbopogon citratus, Citrus sinensis, and Ocimum gratissimum (leaves), is a potential therapy against P. falciparum malaria. In vitro antiplasmodial activities of its constituent solvent extracts were analyzed on CQ-sensitive (3D7) and multidrug resistant (Dd2) P. falciparum strains. The interactions involving the differential solvent extracts were further analyzed using a variable potency ratio drug combination approach. Effective concentration 50 (EC50) values were determined by nonlinear regression curve-fitting of the dose-response data and used in calculating the fractional inhibitory concentration 50 (FIC50) and combination indices (CI) for each pair. The derived EC50 values (3D7/Dd2, µ g/mL) are Nefang-96.96/55.08, MiB-65.33/34.58, MiL-82.56/40.04, Pg-47.02/25.79, Cp-1188/317.5, Cc-723.3/141, Cs-184.4/105.1, and Og-778.5/118.9. Synergism was obtained with MiB/Pg (CI = 0.351), MiL/Pg (0.358), MiB/Cs (0.366), MiL/Cs (0.482), Pg/Cs (0.483), and Cs/Og (0.414) when analyzed at equipotency ratios. Cytotoxicity testing of Nefang and the solvent extracts on two human cell lines (Hep G2 and U2OS) revealed no significant toxicity relative to their antiplasmodial activities (SI > 20). Taken together, our data confirm the antimalarial activities of Nefang and its constituent plant extracts and identified extract pairs with promising synergistic interactions for exploitation towards a rational phytotherapeutic and evidence-based antimalarial drug discovery.


Asunto(s)
Antimaláricos , Malaria Falciparum/tratamiento farmacológico , Extractos Vegetales , Plasmodium falciparum , Solventes/química , Antimaláricos/química , Antimaláricos/farmacología , Evaluación Preclínica de Medicamentos , Células Hep G2 , Humanos , Extractos Vegetales/química , Extractos Vegetales/farmacología
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