According to the World Health Organization, half of the World’s population, approximately 3.3 billion people, is at risk for developing malaria. Nearly 700,000 deaths each year are associated with ...the disease. Control of the disease in humans still relies on chemotherapy. Drug resistance is a limiting factor, and the search for new drugs is important. We have designed and synthesized new 2-(trifluoromethyl)1,2,4triazolo1,5- a pyrimidine derivatives based on bioisosteric replacement of functional groups on the anti-malarial compounds mefloquine and amodiaquine. This approach enabled us to investigate the impact of: (i) ring bioisosteric replacement; (ii) a CF 3 group substituted at the 2-position of the 1,2,4triazolo1,5- a pyrimidine scaffold and (iii) a range of amines as substituents at the 7-position of the of heterocyclic ring; on in vitro activity against Plasmodium falciparum . According to docking simulations, the synthesized compounds are able to interact with P. falciparum dihydroorotate dehydrogenase ( Pf DHODH) through strong hydrogen bonds. The presence of a trifluoromethyl group at the 2-position of the 1,2,4triazolo1,5- a pyrimidine ring led to increased drug activity. Thirteen compounds were found to be active, with IC 50 values ranging from 0.023 to 20 µM in the anti-HRP2 and hypoxanthine assays. The selectivity index (SI) of the most active derivatives 5 , 8 , 11 and 16 was found to vary from 1,003 to 18,478.
According to the World Health Organization, half of the World’s population, approximately 3.3 billion people, is at risk for developing malaria. Nearly 700,000 deaths each year are associated with ...the disease. Control of the disease in humans still relies on chemotherapy. Drug resistance is a limiting factor, and the search for new drugs is important. We have designed and synthesized new 2-(trifluoromethyl)1,2,4triazolo1,5-
a
pyrimidine derivatives based on bioisosteric replacement of functional groups on the anti-malarial compounds mefloquine and amodiaquine. This approach enabled us to investigate the impact of: (i) ring bioisosteric replacement; (ii) a CF
3
group substituted at the 2-position of the 1,2,4triazolo1,5-
a
pyrimidine scaffold and (iii) a range of amines as substituents at the 7-position of the of heterocyclic ring; on
in vitro
activity against
Plasmodium falciparum
. According to docking simulations, the synthesized compounds are able to interact with
P. falciparum
dihydroorotate dehydrogenase (
Pf
DHODH) through strong hydrogen bonds. The presence of a trifluoromethyl group at the 2-position of the 1,2,4triazolo1,5-
a
pyrimidine ring led to increased drug activity. Thirteen compounds were found to be active, with IC
50
values ranging from 0.023 to 20 µM in the anti-HRP2 and hypoxanthine assays. The selectivity index (SI) of the most active derivatives
5
,
8
,
11
and
16
was found to vary from 1,003 to 18,478.
In the title compounds, C7H5F3N4O, (I), and C3H3F3N4·C7H5F3N4O, (II), all of the molecular components exhibit some polarization of their molecular–electronic structures. The molecules in (I) are ...linked into simple C(6) chains, while in (II), the components are linked by a combination of two‐centre N—H⋯N and N—H⋯O, and three‐centre N—H⋯(O,N) hydrogen bonds into chains containing R(5), R(6) and R(8) rings.
Abstract
We present an incremental version (4FGL-DR3, for Data Release 3) of the fourth Fermi Large Area Telescope (LAT) catalog of
γ
-ray sources. Based on the first 12 years of science data in the ...energy range from 50 MeV to 1 TeV, it contains 6658 sources. The analysis improves on that used for the 4FGL catalog over eight years of data: more sources are fit with curved spectra, we introduce a more robust spectral parameterization for pulsars, and we extend the spectral points to 1 TeV. The spectral parameters, spectral energy distributions, and associations are updated for all sources. Light curves are rebuilt for all sources with 1 yr intervals (not 2 month intervals). Among the 5064 original 4FGL sources, 16 were deleted, 112 are formally below the detection threshold over 12 yr (but are kept in the list), while 74 are newly associated, 10 have an improved association, and seven associations were withdrawn. Pulsars are split explicitly between young and millisecond pulsars. Pulsars and binaries newly detected in LAT sources, as well as more than 100 newly classified blazars, are reported. We add three extended sources and 1607 new point sources, mostly just above the detection threshold, among which eight are considered identified, and 699 have a plausible counterpart at other wavelengths. We discuss the degree-scale residuals to the global sky model and clusters of soft unassociated point sources close to the Galactic plane, which are possibly related to limitations of the interstellar emission model and missing extended sources.
Objectives To describe the clinical profile of Brazilian patients with type 2 diabetes attending the public healthcare system and identify factors associated with poor glycaemic control. Design ...Cross-sectional study. Setting 14 centres in five regions of Brazil, including primary care units and outpatient clinics of University Hospitals. Participants Patients with type 2 diabetes attending outpatient clinics of public healthcare system. Main outcome measured Glycated haemoglobin (HbA1c), centrally measured by high-performance liquid chromatography (National Glycohemoglobin Standardization Program certified). Results A total of 5750 patients aged 61±10 years, with 11±8 years of diabetes duration (66% women, 56% non-white, body mass index: 28.0±5.3 kg/m2) were analysed. Mean HbA1c was 8.6±2.2%, and median HbA1c was 8.1% (6.9% to 9.9%). HbA1c <7% was observed in only 26% of patients. Mean HbA1c was higher (p < 0.01) in the North (9.0±2.6%) and Northeast (8.9±2.4%) than in the Midwest (8.1±2%), Southeast (8.4±2.1%) and South regions (8.3±1.9%). Using the cut-off value of HbA1c above the median, age (0.986 (0.983 to 0.989)), white ethnicity (0.931 (0.883 to 0.981)) and being from Midwest region (0.858 (0.745 to 0.989)) were protective factors, while diabetes duration (1.015 (1.012 to 1.018)), use of insulin (1.710 (1.624 to 1.802)) and living in the Northeast region (1.197 (1.085 to 1.321)) were associated with HbA1c >8%. Conclusions The majority of Brazilian patients with type 2 diabetes attending the public healthcare system had HbA1c levels above recommended targets. The recognition of Northeast residents and non-white patients as vulnerable populations should guide future policies and actions to prevent and control diabetes.
Objective: To test the fit of a seven-syndrome model to ratings of preschoolers' problems by parents in very diverse societies. Method: Parents of 19,106 children 18 to 71 months of age from 23 ...societies in Asia, Australasia, Europe, the Middle East, and South America completed the Child Behavior Checklist for Ages 1.5-5 (CBCL/1.5-5). Confirmatory factor analyses were used to test the seven-syndrome model separately for each society. Results: The primary model fit index, the root mean square error of approximation (RMSEA), indicated acceptable to good fit for each society. Although a six-syndrome model combining the Emotionally Reactive and Anxious/Depressed syndromes also fit the data for nine societies, it fit less well than the seven-syndrome model for seven of the nine societies. Other fit indices yielded less consistent results than the RMSEA. Conclusions: The seven-syndrome model provides one way to capture patterns of children's problems that are manifested in ratings by parents from many societies. Clinicians working with preschoolers from these societies can thus assess and describe parents' ratings of behavioral, emotional, and social problems in terms of the seven syndromes. The results illustrate possibilities for culture-general taxonomic constructs of preschool psychopathology. Problems not captured by the CBCL/1.5-5 may form additional syndromes, and other syndrome models may also fit the data. (Contains 2 tables and 1 figure.)
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