Novel acyl thiourea derivatives: Synthesis, antifungal activity, gene toxicity, drug‐like and molecular docking screening

Antypenko, Lyudmyla; Meyer, F.; Kholodniak, O. V.; Sadykova, Zhanar; Jirásková, Tereza; Troianova, Anastasiia; Buhaiova, Vladlena; Cao, Surui; Коваленко, С. И.; Garbe, Leif‐Alexander; Steffens, Karl

doi:10.1002/ardp.201800275

Cited by 29 publications

(17 citation statements)

References 28 publications

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“…Acylthioureas also exhibit good antifungal activity. For example, Antypenko et al reported a series of acylthiourea derivatives with good activity against fungi and Phytophthora pathogens [18]. Qin et al reported that chitosan-based thiourea derivatives containing 1,2,4-triazole heterocycles had good antifungal activity against plant pathogenic bacteria [19].…”

Section: Discussionmentioning

confidence: 99%

Derivatization of Natural Compound β-Pinene Enhances Its In Vitro Antifungal Activity against Plant Pathogens

Shi

Wang

et al. 2019

Molecules

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Background: The development of new antifungal agents has always been a hot research topic in pesticide development. In this study, a series of derivatives of natural compound β-pinene were prepared, and the antifungal activities of these derivatives were evaluated. The purpose of this work is to develop some novel molecules as promising new fungicides. Methods: Through a variety of chemical reactions, β-pinene was transformed into a series of β-pinene-based derivatives containing amide moieties and acylthiourea moieties. The antifungal activities of these derivatives against five plant pathogens including Colletotrichum gloeosporioides, Fusarium proliferatum, Alternaria kikuchiana, Phomopsis sp. and Phytophthora capsici were tested; preliminary structure–activity relationship was discussed. Results: Some derivatives exhibited moderate or significant antifungal activity due to the fusion of the amide moiety or the acylthiourea moiety with the pinane skeleton. The structure–activity relationship analysis showed that the fluorine atom and the strong electron withdrawing nitro group, or trifluoromethyl group on the benzene ring of the derivatives had a significant effect on the improvement of the antifungal activity against Colletotrichum gloeosporioides, Fusarium proliferatum, Alternaria kikuchiana and Phomopsis sp. Meanwhile, the introduction of an ethyl group at the meta-position on the benzene ring of the derivatives could improve the antifungal activity against Phytophthora capsici. Compounds 4e, 4h, 4q, 4r exhibited broad-spectrum antifungal activity against the tested strains. Compound 4o had significant antifungal activity against Phytophthora capsici (IC50 = 0.18 μmol/L). These derivatives were expected to be used as precursor molecules for novel pesticide development in further research.

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Section: Discussionmentioning

confidence: 99%

Derivatization of Natural Compound β-Pinene Enhances Its In Vitro Antifungal Activity against Plant Pathogens

Shi

Wang

et al. 2019

Molecules

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“…To study DHFR-inhibitory and antibacterial activity, N-(R-carbamothioyl)-and N-(Rcarbonyl)hydrazine-1-carbonothioyl)-cycloalkanecarboxamides were selected, the synthesis methods of which are known [11][12][13] and shown in Figure 1 and Table 1.…”

Section: Methodsmentioning

confidence: 99%

1-Cycloalkanecarbonyl-substituted thioureas and thiosemicarbazides as effective dihydrofolate reductase inhibitors with antibacterial activity

et al. 2022

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Search for new antibacterial agents with dihydrofolate reductase-inhibitory activity among N-(R-carbamothiol)cycloalkylcarboxamides using in silico and in vitro methodology, SAR analysis to optimize the synthesis of new potential antinicrobials. Methods. Molecular docking, in vitro DHFR inhibition assay, antimicrobial evaluation, SAR analysis, statistical methods. Results. According to the results of molecular docking to the active center of dihydrofolate reductase (DHFR), namely affinity, the main types of interactions and arrangement in the active center of the enzyme, several N-(R-carbamothioyl)cycloalkylcarboxamides were selected for their inhibitory effect. Based on in vitro screening, few promising compounds with high ability to inhibit DHFR were identified. It was found, that diacylsemicarbazides are more effective inhibitors of DHFR compared to acylthioureas. The studies on antibacterial activity have revealed several promising compounds, namely N-(2-R-hydrazine-1-carbonothioyl)cycloalkanecarboxamides, as highly active antimicrobial agents against E. сoli and St. aureus (MIC 3.125-25.0 μg/ml) with high DHFR-inhibitory effect, the activity of which competes with the comparison drug "Nitrofurazone". This justifies the continuation of systematic research in this direction. Conclusions. A well-founded search among N-(R-carbamothiol)cycloalkylcarboxamides for new antibacterial agents with dihydrofolate reductase-inhibitory activity, using in silico and in vitro methodology, established relationship between the chemical structure and activity aimed at further design of new potential drug agents.

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“…Synthetic studies were conducted according to general approaches to the search for potential biologically active substances, using reagents from Merck (Darmstadt, Germany), Sigma-Aldrich (Missouri, USA) and Enamine (Kyiv, Ukraine). Substituted N-(acylhydrazine-1-carbonotioyl) cycloalkanecarbocamides (1.1-1.14) for the synthetic part of the work were obtained by known methods with constants that correspond to the literature [16][17][18].…”

Section: Methodsmentioning

confidence: 99%

Heterocyclizations based on N-(R-hydrazine-1-carbonothioyl)cycloalkancarboxamides: functionalized azoles and their antimicrobial activity

2022

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Synthesis and structural modification of azoles remains an important area of medical chemistry and allows to obtain new compounds with a wide range of biological activity. Among the significant number of azoles, 1,3,4-thiadiazoles and 1,2,4-triazoles attract special attention, among which are known drugs, larvicides, insecticides, growth regulators, etc. Even though heterocyclizations of functionally substituted hydrazines for their synthesis are well studied, N-(R-hydrazine-1-carbonothioyl)cycloalkanecarboxamides, and nowadays, remain reagents with undiscovered potential. Moreover, the introduction of lipophilic “pharmacophore” fragments (cycloalkanes) in the structure of 1,3,4-thiadiazoles and 1,2,4-triazoles is a promising direction for their modification. That should provide additional intermolecular interactions with enzymes and may lead to enhancement or alteration of the biological activity vector. Thus, the synthesis of new derivatives of this class of compounds and the study of their antibacterial properties remains an urgent problem of medical and organic chemistry. Aim. To investigate the heterocyclization of N-(R-hydrazine-1-carbonothioyl)cycloalkanecarboxa-mides, to establish the structure and antibacterial activity of the synthesized compounds. Materials and methods. Methods of organic synthesis, physical and physical-chemical methods of analysis of organic compounds (NMR 1H-spectroscopy, chromato-mass spectrometry, elemental analysis). The antimicrobial activity of the synthesized compounds was studied according to the generally accepted method for standard strains of microorganisms and fungi. Results. The peculiarities of heterocyclization of N-(R-hydrazine-1-carbonothioyl)cycloalkanecarboxamides have been studied and the factors influencing this reaction have been elucidated. It was shown that these compounds under the conditions of the heterocyclization reaction in concentrated mineral acids form 5-R-2-amino-1,3,4-thiadiazoles. The intermediate undergoes additional hydrolysis by cleavage of the cycloalkanecarboxyl fragment. Alternative methods for the synthesis of 5-R-2-amino-1,3,4-thiadiazoles were proposed. For the first time, the original 4-cycloalkanecarbonyl-3-(amino-,phenyloxo-(thio)methyl-1,5-dihydro-4H-1,2,4-triazole-5-thiones were synthesized by prolonged heating of the corresponding disubstituted thiosemicarbazides. It was not possible to extend this reaction to other diacylthiosemicarbazides, the latter undergo heterocyclization in the presence of sodium hydroxide with the formation of the known 5-R-2,4-dihydro-3H-1,2,4-triazole-3-thiones. 1H NMR spectra were studied, analyzed, and regularities of splitting of characteristic protons in functionalized azoles were established. Conducted microbiological screening was showed that 5-R-2-amino-1,3,4-thiadiazoles, 4-cycloalkanecarbonyl-3-(amino-,phenyloxo-(thio)methyl-1,5-dihydro-4H-1,2,4-triazole-5-thiones and 5-R-2,4-dihydro-3H-1,2,4-triazole-3-thione were less effective antibacterial and antifungal agents (MIC 100–200 μg/ml) compared with N-(R-hydrazine-1-carbonothioyl)cycloalkanecarboxamides (MIC 3.125–200 μg/ml). Conclusions. It was found that N-(R-hydrazine-1-carbonotioyl)cycloalkane-carboxamides, depending on the conditions of heterocyclization form 5-R-2-amino-1,3,4-thiadiazoles, 3-(phenyloxo-(thio)methyl-1,5-dihydro-4H-1,2,4-triazole-5-thiones or 5-R-2,4-dihydro-3H-1,2,4-triazole-3-thiones. It was established that synthesized azoles were shown less effective antimicrobial and antifungal activity in comparison with N-(R-hydrazine-1-carbonothioyl)cycloalkanecarboxamides.

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Novel acyl thiourea derivatives: Synthesis, antifungal activity, gene toxicity, drug‐like and molecular docking screening

Cited by 29 publications

References 28 publications

Derivatization of Natural Compound β-Pinene Enhances Its In Vitro Antifungal Activity against Plant Pathogens

Derivatization of Natural Compound β-Pinene Enhances Its In Vitro Antifungal Activity against Plant Pathogens

1-Cycloalkanecarbonyl-substituted thioureas and thiosemicarbazides as effective dihydrofolate reductase inhibitors with antibacterial activity

Heterocyclizations based on N-(R-hydrazine-1-carbonothioyl)cycloalkancarboxamides: functionalized azoles and their antimicrobial activity

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