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Filename: controllers/Detail.php
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The World Health Organization (WHO) estimated that there were 247 million malaria cases in 2021 worldwide, representing an increase in 2 million cases compared to 2020. The urgent need for the development of new antimalarials is underscored by specific criteria, including the requirement of new modes of action that avoid cross-drug resistance, the ability to provide single-dose cures, and efficacy against both assexual and sexual blood stages. Motivated by the promising results obtained from our research group with [1,2,4]triazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine derivatives, we selected these molecular scaffolds as the foundation for designing two new series of piperaquine analogs as potential antimalarial candidates. The initial series of hybrids was designed by substituting one quinolinic ring of piperaquine with the 1,2,4-triazolo[1,5-a]pyrimidine or pyrazolo[1,5-a]pyrimidine nucleus. To connect the heterocyclic systems, spacers with 3, 4, or 7 methylene carbons were introduced at the 4 position of the quinoline. In the second series, we used piperazine as a spacer to link the 1,2,4-triazolo[1,5-a]pyrimidine or pyrazolo[1,5-a]pyrimidine group to the quinoline core, effectively merging both pharmacophoric groups via a rigid spacer. Our research efforts yielded promising compounds characterized by low cytotoxicity and selectivity indices exceeding 1570. These compounds displayed potent in vitro inhibitory activity in the low nanomolar range against the erythrocytic form of the parasite, encompassing both susceptible and resistant strains. Notably, these compounds did not show cross-resistance with either chloroquine or established P. falciparum inhibitors. Even though they share a pyrazolo- or triazolo-pyrimidine core, enzymatic inhibition assays revealed that these compounds had minimal inhibitory effects on PfDHODH, indicating a distinct mode of action unrelated to targeting this enzyme. We further assessed the compounds' potential to interfere with gametocyte and ookinete infectivity using mature P. falciparum gametocytes cultured in vitro. Four compounds demonstrated significant gametocyte inhibition ranging from 58 % to 86 %, suggesting potential transmission blocking activity. Finally, we evaluated the druggability of these new compounds using in silico methods, and the results indicated that these analogs had favorable physicochemical and ADME (absorption, distribution, metabolism, and excretion) properties. In summary, our research has successfully identified and characterized new piperaquine analogs based on [1,2,4]triazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine scaffolds and has demonstrated their potential as promising candidates for the development of antimalarial drugs with distinct mechanisms of action, considerable selectivity, and P. falciparum transmission blocking activity.
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http://dx.doi.org/10.1016/j.ejmech.2024.116163 | DOI Listing |
Voltage-sensitive calcium channels contribute to depolarization of both motor- and interneurons in animal studies, but less is known of their contribution to human motor control and whether blocking them has potential in future antispasmodic treatment in humans. Therefore, this study investigated the acute effect of Nimodipine on the transmission of human spinal reflex pathways involved in spasticity. In a double-blinded, cross-over study, we measured soleus muscle stretch- and H-reflexes, and tibialis anterior cutaneous reflexes in nineteen healthy subjects before and after Nimodipine (tab-let 60mg) or Baclofen (tablet 25mg).
View Article and Find Full Text PDFPlast Reconstr Surg Glob Open
December 2024
From the Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School Hospital, Tokyo, Japan.
Background: Keloids are growing scars that arise from injury to the reticular dermis and subsequent chronic local inflammation. The latter may be promoted by vascular hyperpermeability, which permits the ingress of chronic inflammatory cells/factors. Cutaneous capillaries consist of endothelial cells that generate, and are anchored by, a vascular basement membrane (VBM).
View Article and Find Full Text PDFProtein Pept Lett
December 2024
Department of Pharm. Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India.
Alzheimer's disease (AD) treatments currently available have ineffective results. Previously employed Acetylcholine esterase inhibitors and memantine, an NMDA receptor antagonist, target a single target structure that plays a complex role in the multifactorial progression of disease. Memantine moderates the toxic effects of excessive glutamate activity by blocking NMDA receptors, which decreases neurotoxicity in AD, while acetylcholine esterase inhibitors function by blocking cholinergic receptors (muscarinic and nicotinic), preventing the breakdown of acetylcholine, thereby enhancing cholinergic transmission, thus improving cognitive functions in mild to moderate stages of AD.
View Article and Find Full Text PDFBMC Biol
December 2024
State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
Background: The mucus layer provides the first defense that keeps the epithelium free from microorganisms. However, the effect of the small intestinal mucus layer on pathogen invasion is still poorly understood, especially for swine enteric coronavirus. To better understand virus‒mucus layer‒intestinal epithelium interactions, here, we developed a porcine intestinal organoid mucus‒monolayer model under air‒liquid interface (ALI) conditions.
View Article and Find Full Text PDFJ Magn Reson Open
June 2024
Department of Chemistry, University of California, Irvine 92697-2025.
In this tutorial paper, we describe some basic principles and practical considerations for designing probe circuits for NMR or MRI. The goal is building a bridge from material that is familiar from undergraduate physics courses to more specialized information needed to put together and tune a resonant circuit for magnetic resonance. After a brief overview of DC and AC circuits, we discuss the properties of circuit elements used in an NMR probe and how they can be assembled into building blocks for multi-channel circuits.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!