Novel naphthylamide derivatives as dual-target antifungal inhibitors: Design, synthesis and biological evaluation

An, Yunfei; Dong, Yue; Liu, Min; Han, Jun; Zhao, Liyu; Sun, Bin

doi:10.1016/j.ejmech.2020.112991

Cited by 23 publications

(18 citation statements)

References 44 publications

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“…Total sterols of C. neoformans H99 cells were extracted after treatment with compound D16 at 3 μg/mL. Total ERG enzymes, compound D16 , and total sterols were added to reaction buffer [50 mM Tris-HCl (pH 7.4), 150 mM KCl, 10 mM MgCl 2 , and 2 mM NADPH] . The samples were incubated at 37 °C for 24 h. The transformation of sterol was analyzed by GC-MS.…”

Section: Methodsmentioning

confidence: 99%

Discovery of Novel Sertraline Derivatives as Potent Anti-Cryptococcus Agents

Yun

et al. 2022

J. Med. Chem.

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Treatment of life-threatening cryptococcal meningitis (CM) is highly challenging due to the limited efficacy of the available antifungal drugs. Antidepressant sertraline (SER) has been proposed to be a potential antifungal agent for CM. However, clinical studies indicated that SER failed to achieve the expected therapeutic effects. Herein, novel SER derivatives were designed by scaffold hopping, and they showed improved anticryptococcal activity both in vitro and in vivo. In particular, compound D16 was identified as a promising anti-CM agent with a new antifungal mode of action. It acted by blocking the biosynthesis of ergosterol through the inhibition of Δ5,6-desaturase. This study provides a new target and a drug-like candidate for CM treatment.

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Section: Methodsmentioning

confidence: 99%

Discovery of Novel Sertraline Derivatives as Potent Anti-Cryptococcus Agents

Yun

et al. 2022

J. Med. Chem.

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“…Ligands with clear binding modes can be preferentially selected as lead compounds. X-ray structure information is essential for identifying the key pharmacophore elements, such as crucial hydrogen bonds, charges, and hydrophobic groups. , If the selected ligands have structural similarities, including similar functional groups or molecular backbones, the merged-pharmacophore method can be employed to make the pharmacophores overlap with each other.…”

Section: Rational Design Of Multitargeted Ligandsmentioning

confidence: 99%

Rational Multitargeted Drug Design Strategy from the Perspective of a Medicinal Chemist

Liu

et al. 2021

J. Med. Chem.

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The development of multitarget-directed ligands (MTDLs) has become a widely focused research topic, but rational design remains as an enormous challenge. This paper reviews and discusses the design strategy of incorporating the second activity into an existing single-active ligand. If the binding sites of both targets share similar endogenous substrates, MTDLs can be designed by merging two lead compounds with similar functional groups. If the binding sites are large or adjacent to the solution, two key pharmacophores can be fused directly. If the binding regions are small and deep inside the proteins, the linkedpharmacophore strategy might be the only way. The added pharmacophores of second targets should not affect the binding mode of the original ones. Moreover, the inhibitory activities of the two targets need to be adjusted to achieve an optimal ratio.

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“…The efficacy of combination treatments heavily relies on the pharmacokinetic and pharmacodynamic properties of each of the drugs in the combination. 52 Moreover, COX-inhibiting drugs are known to induce gastrointestinal irritation. COX-1 is mainly responsible for mucus formation in the gastrointestinal tract and its inhibition is therefore blamed for inducing irritation.…”

Section: Introductionmentioning

confidence: 99%

Fluconazole-COX Inhibitor Hybrids: A Dual-Acting Class of Antifungal Azoles

2022

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When used in combination with azole antifungal drugs, cyclooxygenase (COX) inhibitors such as ibuprofen improve antifungal efficacy. We report the conjugation of a chiral antifungal azole pharmacophore to COX inhibitors and the evaluation of activity of 24 hybrids. Hybrids derived from ibuprofen and flurbiprofen were considerably more potent than fluconazole and comparable to voriconazole against a panel of Candida species. The potencies of hybrids composed of an S -configured azole pharmacophore were higher than those with an R -configured pharmacophore. Tolerance, defined as the ability of a subpopulation of cells to grow in the presence of the drug, to the hybrids was lower than to fluconazole and voriconazole. The hybrids were active against a mutant lacking CYP51, the target of azole drugs, indicating that these agents act via a dual mode of action. This study established that azole-COX inhibitor hybrids are a novel class of potent antifungals with clinical potential.

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Novel naphthylamide derivatives as dual-target antifungal inhibitors: Design, synthesis and biological evaluation

Cited by 23 publications

References 44 publications

Discovery of Novel Sertraline Derivatives as Potent Anti-Cryptococcus Agents

Discovery of Novel Sertraline Derivatives as Potent Anti-Cryptococcus Agents

Rational Multitargeted Drug Design Strategy from the Perspective of a Medicinal Chemist

Fluconazole-COX Inhibitor Hybrids: A Dual-Acting Class of Antifungal Azoles

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