Synthesis, structure, and antibacterial evaluation of new <i>N</i>‐substituted‐3‐amino‐ 5‐oxo‐4‐phenyl‐2,5‐dihydro‐1<i>H</i>‐pyrazole‐1‐carbothioamides

Pitucha, Monika; Mazur, Liliana; Kosikowska, Urszula; Pachuta‐Stec, Anna; Malm, Anna; Popiołek, Łukasz; Rzączyńska, Z.

doi:10.1002/hc.20598

Cited by 7 publications

(5 citation statements)

References 22 publications

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“…Herein, various substitutions were introduced on the aromatic scaffold and the urea group was designed as the linker to obtain cyanoacetylhydrazine carbothioamide and cyanoacetylhydrazine carboxamide derivatives, respectively (compounds A2 – A12 and A13–A14 , Figure ). Interestingly, we found the cyanoacetylhydrazine group was prone to self-cyclizing into pyrazoldone in alkaline or acid medium. , Thus, the cyclization of compounds A1 – A8 gave pyrazolone carbothioamide derivatives B1 – B8 (Figure ).…”

Section: Resultsmentioning

confidence: 93%

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Discovery of Pyrazolone Carbothioamide Derivatives as Inhibitors of the Pdr1-KIX Interaction for Combinational Treatment of Azole-Resistant Candidiasis

Wang

Yang

et al. 2023

J. Med. Chem.

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Candida glabrata has emerged as an important opportunistic pathogen of invasive candidiasis due to increasing drug resistance. Targeting Pdr1-KIX interactions with small molecules represents a potential strategy for treating drug-resistant candidiasis. However, effective Pdr1-KIX inhibitors are rather limited, hindering the validation of target druggability. Here, new Pdr1-KIX inhibitors were designed and assayed. Particularly, compound B8 possessed a new chemical scaffold and exhibited potent KIX binding affinity, leading to enhanced synergistic efficacy with fluconazole to treat resistant C. glabrata infection (FICI = 0.28). Compound B8 acted by inhibiting the efflux pump and down-regulating resistance-associated genes through blocking the Pdr1-KIX interaction. Compound B8 exhibited excellent in vitro and in vivo antifungal potency in combination with fluconazole against azole-resistant C. glabrata. It also had direct antifungal effect to treat C. glabrata infection, suggesting new mechanisms of action independent of Pdr1-KIX inhibition. Therefore, compound B8 represents a promising lead compound for antifungal drug development.

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Section: Resultsmentioning

confidence: 93%

“…Interestingly, we found the cyanoacetylhydrazine group was prone to self-cyclizing into pyrazoldone in alkaline or acid medium. 26,27 Thus, the cyclization of compounds A1−A8 gave pyrazolone carbothioamide derivatives B1−B8 (Figure 1). Chemistry.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Pyrazolone Carbothioamide Derivatives as Inhibitors of the Pdr1-KIX Interaction for Combinational Treatment of Azole-Resistant Candidiasis

Wang

Yang

et al. 2023

J. Med. Chem.

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“…Three N -substituted-3-amino-5-oxo-4-phenyl-2,5-dihydro-1 H -pyrazole-1-carbothioamide derivatives have been screened for the antibacterial investigations. Obtained compounds were characterized and described earlier (Pitucha et al , 2010 ).…”

Section: Methodsmentioning

confidence: 99%

“…Much attention has been paid to pyrazole derivatives due to their wide range of antibacterial activities as potential and selective inhibitors against DNA gyrase capable of causing bacterial cells’ death (Reece and Maxwell, 1991 ; Maxwell, 1997 ; Tanitame et al , 2004 ; Liu et al , 2008 ; Shiroya et al , 2011 ). N -ethyl-3-amino-5-oxo-4-phenyl-2,5-dihydro-1 H -pyrazole-1-carbothioamide, synthesized according to Pitucha et al ( 2010 ) appears to be a promising precursor of agents with good activity mainly against Gram-positive bacteria––both pathogenic, including Staphylococcus aureus (MIC = 7.81–62.5 μg ml −1 ) as well as opportunistic, e.g., S. epidermidis , Bacillus spp. or Micrococcus luteus with MIC = 3.91–31.25 μg ml −1 (Pitucha et al , 2010 ).…”

Section: Introductionmentioning

confidence: 99%

“…N -ethyl-3-amino-5-oxo-4-phenyl-2,5-dihydro-1 H -pyrazole-1-carbothioamide, synthesized according to Pitucha et al ( 2010 ) appears to be a promising precursor of agents with good activity mainly against Gram-positive bacteria––both pathogenic, including Staphylococcus aureus (MIC = 7.81–62.5 μg ml −1 ) as well as opportunistic, e.g., S. epidermidis , Bacillus spp. or Micrococcus luteus with MIC = 3.91–31.25 μg ml −1 (Pitucha et al , 2010 ). The inhibitory effect against Gram-negative bacteria––belonging to Enterobacteriaceae family ( Escherichia coli , Klebsiella pneumoniae , and Proteus mirabilis ) or nonfermentative rods ( Pseudomonas aeruginosa ) was weaker (MIC = 250–1,000 μg ml −1 ).…”

Section: Introductionmentioning

confidence: 99%

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Inhibitory effect of N-ethyl-3-amino-5-oxo-4-phenyl-2,5-dihydro-1H-pyrazole-1-carbothioamide on Haemophilus spp. planktonic or biofilm-forming cells

et al. 2013

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During this study, we have investigated in vitro activity of N-substituted-3-amino-5-oxo-4-phenyl-2,5-dihydro-1H-pyrazole-1-carbothioamide derivatives with N-ethyl, N-(4-metoxyphenyl) and N-cyclohexyl substituents against Gram-negative Haemophilus influenzae and H. parainfluenzae bacteria. A spectrophotometric assay was used in order to determine the bacterial growth and biofilm formation using a microtiter plate to estimate minimal inhibitory concentration (MIC) and minimal biofilm inhibitory concentration (MBIC). Among the tested N-substituted pyrazole derivatives, only N-ethyl-3-amino-5-oxo-4-phenyl-2,5-dihydro-1H-pyrazole-1-carbothioamide showed a significant in vitro activity against both planktonic cells of H. parainfluenzae (MIC = 0.49–31.25 μg ml−1) and H. influenzae (MIC = 0.24–31.25 μg ml−1) as well as biofilm-forming cells of H. parainfluenzae (MBIC = 0.24–31.25 μg ml−1) and H. influenzae (MBIC = 0.49 to ≥31.25 μg ml−1). The pyrazole compound exerted higher inhibitory effect both on the growth of planktonic cells and biofilm formation by penicillinase-positive and penicillinase-negative isolates of H. parainfluenzae than the activity of commonly used antibiotics such as ampicillin. No cytotoxicity of the tested compound in vitro at concentrations used was found. The tested pyrazole N-ethyl derivative could be considered as a compound for the design of agents active against both pathogenic H. influenzae and opportunistic H. parainfluenzae, showing also anti-biofilm activity. This appears important because biofilms are determinants of bacterial persistence in long-term and recurrent infections recalcitrant to standard therapy.

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ChemInform Abstract: Synthesis, Structure, and Antibacterial Evaluation of New N‐Substituted‐3‐amino‐5‐oxo‐4‐phenyl‐2,5‐dihydro‐1H‐pyrazole‐1‐carbothio amides.

et al. 2010

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The title compounds (IV) and (VI) are synthesized via two methods. Compounds (IV) are obtained in the cyclization reaction of thiosemicarbazide (III), whilst compound (VI) is obtained from the direct reaction of hydrazide (I) with isothiocyanate (V). Some of the compounds possess promising antibacterial activities. -(PITUCHA*, M.; MAZUR, L.; KOSIKOWSKA, U.; PACHUTA-STEC, A.; MALM, A.; POPIOLEK, L.; RZACZYNSKA, Z.; Heteroat. Chem. 21 (2010) 4, 215-221,

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Synthesis, structure, and antibacterial evaluation of new N‐substituted‐3‐amino‐ 5‐oxo‐4‐phenyl‐2,5‐dihydro‐1H‐pyrazole‐1‐carbothioamides

Abstract: ABSTRACT:

Cited by 7 publications

References 22 publications

Discovery of Pyrazolone Carbothioamide Derivatives as Inhibitors of the Pdr1-KIX Interaction for Combinational Treatment of Azole-Resistant Candidiasis

Discovery of Pyrazolone Carbothioamide Derivatives as Inhibitors of the Pdr1-KIX Interaction for Combinational Treatment of Azole-Resistant Candidiasis

Inhibitory effect of N-ethyl-3-amino-5-oxo-4-phenyl-2,5-dihydro-1H-pyrazole-1-carbothioamide on Haemophilus spp. planktonic or biofilm-forming cells

ChemInform Abstract: Synthesis, Structure, and Antibacterial Evaluation of New N‐Substituted‐3‐amino‐5‐oxo‐4‐phenyl‐2,5‐dihydro‐1H‐pyrazole‐1‐carbothio amides.

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