Discovery of Potent and Fast-Acting Antimalarial Bis-1,2,4-triazines

Priebbenow, Daniel L.; Mathiew, Mitch; Shi, Da–Hua; Harjani, Jitendra R.; Beveridge, Julia G.; Chavchich, Marina; Edstein, Michael D.; Duffy, Sandra; Avery, Vicky M.; Jacobs, Robert T.; Brand, Stephen; Shackleford, David M.; Wang, Wen; Zhong, Longjin; Lee, Given; Tay, Erin; Barker, Helena; Crighton, Elly; White, Karen L.; Charman, Susan A.; Paoli, Amanda De; Creek, Darren J.; Baell, Jonathan B.

doi:10.1021/acs.jmedchem.1c00044

Cited by 15 publications

(3 citation statements)

References 34 publications

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“…Furthermore, a crystallographic experimental approach known as "Selected Area (Electron) Diffraction (SAED) pattern enclosed bright circular patches that corroborated the polycrystalline nature, implying that the CuO particles have various crystallographic directions, as seen in Fig. 2c 23 .…”

Section: Resultsmentioning

confidence: 77%

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CuO nanoparticles for green synthesis of significant anti-Helicobacter pylori compounds with in silico studies

Shehab,

Elsayed,

Abdel Hamid

et al. 2024

Sci Rep

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Helicobacter pylori (H. pylori) is a universal health intimidation as mentioned by the World Health Organization. The primary causal agent linked to a number of illnesses, including inflammation and the development of stomach ulcers, is Helicobacter pylori. Since, H. pylori develops antibiotic resistance quickly, current H. pylori treatment approaches are becoming less effective. Our research aims to highlight novel formulation antibiotics using CuO-NPs as catalysts and studied their activity as anti-helicobacter pylori supported by computational studies (POM analysis and molecular docking) software. They were designed for anti-Helicobacter Pylori action. All compounds revealed a bactericidal effect better than the reference McFarland standards.

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Section: Resultsmentioning

confidence: 77%

“…2a and b). Particles were made up of a sheet-like building structure 23 . The nanoparticles coincided with one other which greatly aided the growth of the flower like nanostructure together with oval and spherical outlines 24 .…”

Section: Resultsmentioning

confidence: 99%

CuO nanoparticles for green synthesis of significant anti-Helicobacter pylori compounds with in silico studies

Shehab,

Elsayed,

Abdel Hamid

et al. 2024

Sci Rep

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“…A lead triazine dimer MIPS-0004373 (Fig. 1) was shown to be highly active in vitro against P. falciparum with singledigit nanomolar activity and up to several thousand-fold lower toxicity to mammalian cells, thus demonstrating excellent selectivity (6,7). Furthermore, it was shown to be equipotent against chloroquine and artemisinin resistant laboratory strains of P. falciparum, and field isolates of P. falciparum and P. vivax (8).…”

Section: Introductionmentioning

confidence: 99%

The Novel bis-1,2,4-Triazine MIPS-0004373 Demonstrates Rapid and Potent Activity against All Blood Stages of the Malaria Parasite

Ellis

Lucantoni

Chavchich³

et al. 2021

Antimicrob Agents Chemother

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Novel bis-1,2,4-triazine compounds with potent in vitro activity against Plasmodium falciparum parasites were recently identified. The bis-1,2,4-triazines represent a unique antimalarial pharmacophore, and are proposed to act by a novel, but as-yet-unknown mechanism of action. This study investigated the activity of the bis-1,2,4-triazine, MIPS-0004373, across the mammalian lifecycle stages of the parasite, and profiled the kinetics of activity against blood and transmission-stage parasites in vitro and in vivo . MIPS-0004373 demonstrated rapid and potent activity against P. falciparum , with excellent in vitro activity against all asexual blood stages. Prolonged in vitro drug exposure failed to generate stable resistance de novo , suggesting a low propensity for the emergence of resistance. Excellent activity was observed against sexually-committed ring stage parasites, but activity against mature gametocytes was limited to inhibiting male gametogenesis. Assessment of liver stage activity demonstrated good activity in an in vitro P. berghei model, but no activity against P. cynomolgi hypnozoites or liver schizonts. The bis-1,2,4-triazine, MIPS-0004373, efficiently cleared an established P. berghei infection in vivo , with efficacy similar to artesunate and chloroquine, and a recrudescence profile comparable to chloroquine. This study demonstrates the suitability of bis-1,2,4-triazines for further development towards a novel treatment for acute malaria.

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Exploring the Recent Pioneering Developments of Small Molecules in Antimalarial Drug Armamentarium: A Chemistry Prospective Appraisal

Bagratee,

Prawlall,

Ndlovu

et al. 2024

Chemistry & Biodiversity

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Malaria is a very destructive and lethal parasitic disease that causes significant mortality worldwide, resulting in the loss of millions of lives annually. The uncontrolled intake of antimalarial drugs often employed in clinical settings has resulted in the emergence of numerous strains of plasmodium that are resistant to these drugs, including multidrug‐resistant strains. Hence, there is an urgent need for developing unique classes of antimalarial drugs that function with distinct mechanisms of action. In this context, the design and development of hybrid compounds that combine pharmacophoric properties from different lead molecules into a single unit gives a unique perspective towards further development of malaria drugs in the next generation. In light of this, we have reviewed the progress of hybrid antimalarial agents from 2021 up to the present. This manuscript presents a comprehensive overview of the latest advancements in the medicinal chemistry pertaining to small molecules, with a specific focus on their potential as antimalarial agents. This review explores a variety of physiologically active compounds that have been described in the literature in order to lay a strong foundation for the logical design and eventual identification of antimalarial drugs based on lead frameworks.

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Discovery of Potent and Fast-Acting Antimalarial Bis-1,2,4-triazines

Cited by 15 publications

References 34 publications

CuO nanoparticles for green synthesis of significant anti-Helicobacter pylori compounds with in silico studies

CuO nanoparticles for green synthesis of significant anti-Helicobacter pylori compounds with in silico studies

The Novel bis-1,2,4-Triazine MIPS-0004373 Demonstrates Rapid and Potent Activity against All Blood Stages of the Malaria Parasite

Exploring the Recent Pioneering Developments of Small Molecules in Antimalarial Drug Armamentarium: A Chemistry Prospective Appraisal

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