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Synthesis and Antitrypanosomal and Mechanistic Studies of a Series of 2-Arylquinazolin-4-hydrazines: A Hydrazine Moiety as a Selective, Safe, and Specific Pharmacophore to Design Antitrypanosomal Agents Targeting NO Release. | LitMetric

AI Article Synopsis

  • Nitric oxide (NO) is a promising target for creating new medications against trypanosomatid parasites due to its high toxicity to these organisms and low harm to host cells.
  • Researchers designed a new class of NO-donors using 2-arylquinazolin-4-hydrazine, which disrupts parasite folate metabolism and exhibits strong leishmanicidal activity along with low toxicity.
  • Mechanistic studies demonstrated that these compounds can release NO and act as antifolate agents, with their effectiveness validated through various tests, indicating their potential as safe treatments against trypanosomiasis.

Article Abstract

Nitric oxide (NO) represents a valuable target to design antitrypanosomal agents by its high toxicity against trypanosomatids and minimal side effects on host macrophages. The progress of NO-donors as antitrypanosomal has been restricted by the high toxicity of their agents, which usually is based on NO-heterocycles and metallic NO-complexes. Herein, we carried out the design of a new class of NO-donors based on the susceptibility of the hydrazine moiety connected to an electron-deficient ring to be reduced to the amine moiety with release of NO. Then, a series of novel 2-arylquinazolin-4-hydrazine, with the potential ability to disrupt the parasite folate metabolism, were synthesized. Their in vitro evaluation against and parasites and mechanistic aspects were investigated. The compounds displayed significant leishmanicidal activity, identifying three potential candidates, that is, , , and , for further assays by their good antiamastigote activities against , low toxicity, non-mutagenicity, and good ADME profile. Against parasites, derivatives , , and displayed interesting levels of activities and selectivities. Mechanistic studies revealed that the 2-arylquinazolin-4-hydrazines act as either antifolate or NO-donor agents. NMR, fluorescence, and theoretical studies supported the fact that the quinazolin-hydrazine decomposed easily in an oxidative environment via cleavage of the N-N bond to release the corresponding heterocyclic-amine and NO. Generation of NO from axenic parasites was confirmed by the Griess test. All the evidence showed the potential of hydrazine connected to the electron-deficient ring to design effective and safe NO-donors against trypanosomatids.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9773939PMC
http://dx.doi.org/10.1021/acsomega.2c06455DOI Listing

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