A synthesis method of novel N‐cycloalkylcarbonyl‐N′‐arylthioureas was developed. It consists of sequential addition of equimolecular amounts of ammonium isothiocyanate and substituted anilines to cycloalkylcarbonyl chlorides. The identity and purity of products were confirmed by LC/MS spectra, their structure by elemental analysis, IR and 1H‐NMR spectra. Preliminary antimicrobial screening for standard microorganisms and molecular docking allowed to select several structures for antifungal and genetic toxicity studies. Conducted in vitro screening of 9 compounds for antifungal potential against 11 phytopathogenic fungi and three Phytophthora strains revealed that two N‐(arylcarbamothioyl) cyclopropanecarboxamides at a concentration of 50 μg/ml exhibited activities comparable to the standard antifungal agent ‘Cyproconazole’. Analysis of mutagenicity of novel thioureas using the Salmonella reverse mutagenicity assay (‘Ames Test’) showed a low gene‐toxicity profile.
Nine novel acyl thioureas were synthesized. Their identities and purities were confirmed by LC-MS spectra; each structure was elucidated by elemental analysis, IR, 1 Н and 13 C NMR spectra. Applying an in vitro screening of their antifungal potential, three substances (3, 5, and 6) could be selected as showing high activity against 11 fungi and 3 Phytophthora strains of phytopathogenic significance. Analysis of gene toxicity with the Salmonella reverse mutagenicity test, as an assessment of drug likeness, lipophilicity, and calculations of frontier molecular orbitals assign a low toxicity profile to these compounds. Molecular docking studies point to 14α-demethylase (CYP51) and N-myristoyltransferase (NMT) as possible fungal targets for growth inhibition. The findings are discussed with respect to structure-activity relationship (SAR).
A targeted search for anticonvulsant agents among unknown diacylthiosemicarbazides with the analysis of the structure-activity relationship (SAR-analysis). Methods. Organic synthesis; molecular docking; spectral methods; pentylenetetrazole convulsions, statistical methods. Results. A strategy of search for new anticonvulsant agents among unknown diacylthiosemicarbazides has been developed. It included virtual-oriented screening towards [the] active centers of enzymes and sodium channels that underlie the mechanism of antiepileptic drugs activity. The synthesis of diacylthiosemicarbazides was carried out by the in situ method, namely, accomplishing the interaction of cycloalkanecarbonyl chlorides with ammonium isothiocyanate and the subsequent nucleophilic addition of cycloalkyl-(aralkyl-, aryl-, hetaryl-) carboxylic acid hydrazides. The peculiarities of the structure of the synthesized compounds were confirmed by spectral methods (LCMS and 1 H NMR spectra). Biological screening showed that diacylthiosemicarbazides (2) in the experimental model of pentyleneterazole seizures in rats increased the latency period of seizures by 2.77-7.82 times, reduced the duration of tonic-clonic seizures by 1.23-5.59 minutes and prevented mortality by 30-60 %, relative to the control group of animals. It was shown that diacylthiosemicarbazides (2.6, 2.15, 2.22, 2.18) with cyclopropane-or cyclopentanecarboxamide groups show the anticonvulsant activity that exceeds that of the reference drug Depakine or competes with it. Conclusions. A range of new diacylthiosemicarbazides were obtained and the primary screening of their anticonvulsant activity was performed, the SAR-analysis was provided, and the hit-compound was identified for further in-depth pharmacological studies.
Acylisothiocyanates are a promising class of organic compounds that are present in the plant world and can be used in the synthesis of disubstituted thioureas and various heterocycles. These derivatives are characterized by growth-regulating, antibacterial, fungicidal, cytotoxicity, and other activities. Modification of acylisothiocyanates by fragments of substituted aminoarylcarboxylic (sulfo) acids is promising, as some of them (anthranilic, p-aminobenzoic acids) are precursors for the auxins and other natural compounds synthesis. Their combined activity is also an important aspect. Namely the simultaneous manifestation of both fungicidal and restrictive activity. Based on this, the synthesis of new substituted (cycloalkylcarbonylthioureido)aryl-(benzyl-)carboxylic (sulfonic) acids is relevant as promising regulators of plant growth with antibacterial activity. The aim of this work is to search for effective compounds with growth-regulating and antimicrobial activity among substituted (cycloalkylcarbonylthioureido)aryl-(benzyl-)carboxylic (sulfonic) acids. Materials and methods. Methods of organic synthesis, physical and physical-chemical methods of analysis of organic compounds (IR, NMR 1H-spectroscopy, chromato-mass spectrometry, elemental analysis). Antimicrobial activity studies were performed on standard strains of bacteria and fungi (S. aureus ATCC 25923, E. coli ATCC 25922, P. aeruginosa ATCC 27853 and C. albicans ATCC 885-653). The effect of synthesized compounds on growth rates was evaluated on wheat (variety Grom). Results. An “in situ” method for the synthesis of substituted (cycloalkylcarbonylthioureido)aryl-(benzyl-)carboxylic (sulfonic) acids was proposed. It was shown that the latter could be easily synthesized by the sequential interaction of cyclopropanecarbonyl chloride, ammonium isothiocyanate, and aminoaryl-(benzyl-)carboxylic, sulfanilic acids or sulfamide. Data of 1H NMR spectra showed the peculiarities of the structure of the synthesized compounds, namely the presence of singlet signals of protons of urea, thioamide and carboxyl groups, multiple signals of methine and methylene protons of cyclopropane fragment. It was found that the synthesized compounds showed moderate antimicrobial activity against S. aureus and P. aeruginosa (MIC 50 μg/ml, MBC 100 μg/ml) and significant antifungal activity against C. albicans (MIC 25–50 μg/ml, MFC 25–50 μg/ml). A number of compounds were identified as effective regulators of wheat growth and exceed the natural analogue – heteroauxin (3-indolylacetic acid) in terms of auxin-like activity. Conclusions. A one-step method for the synthesis of substituted (cyclopropanecarbonylthioureido)aryl-(benzyl-)carboxylic (sulfonic) acids was developed. The physical-chemical properties of the synthesized compounds were studied using a set of methods (IR, 1H NMR spectroscopy, chromato-mass spectrometry, elemental analysis) and the features of the structure were discussed. The synthesized compounds reveal moderate antimicrobial, high antifungal activity, and growth-promoting activity.
Acyl isothiocyanates and their functional derivatives (acyl thioureas and acyl thiosemicarbazides) are an important group of organic compounds that are widely used in the synthesis of heterocycles and in chemistry as catalysts, ligands, colorimetric hemosensors, etc. In recent years, there has been an increased interest towards this class of compounds as promising biologically active compounds, especially since the latest advances in medicinal chemistry for them are not sufficiently studied. The aim. To summarize and systematize information for the last 10 years on methods of synthesis and biological activity of substituted acyl thioureas and acyl thiosemicarbazides. Materials and methods. Web-tools for finding scientific information (Reaxys, Scopus, Google Scholar, ScienceResearch, SciFinder, Web of Science, etc.). Results and discussion. Literature sources related to the methods of synthesis of substituted acyl thioureas and acyl thiosemicarbazides were systematized and analyzed. The main approaches for the formation of these compounds are revealed: stepwise formation from carboxylic acids, through acyl chlorides and acyl isothiocyanates followed by nucleophilic addition of amines or hydrazides of carboxylic acids ("one-pot synthesis"), nucleophilic addition of amines or hydrazides of carboxylic acids directly to acyl isothiocyanates and parallel microwave synthesis using acyl isothiocyanates and amines as reagents. The possibility of their use as ligands for the formation of complex compounds with transition metal ions was discussed. In the review biological activity of these structures, namely antimicrobial, fungicidal, antitumor, antiviral, antifungal and other activities was detailazed. Conclusions. The basic approaches to the synthesis of substituted acylthuoureas and acyl thiosemicarbazides which include the application of carboxylic acids, their derivatives (acyl halides and isothiocyanates) and N-nucleophiles as initial compounds were discussed. It was shown that aforementioned class of the compounds reveals the versatile biological activity and are promising for further structural modification aimed to the search of novel drugs
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.
Вступ. Тривале застосування діуретиків, особливо у великих дозах, численність і тяжкість побічних ефектів (водно-електролітні й метаболічні порушення), а також відносно обмежена номенклатура існуючих діуретичних засобів диктують необхідність пошуку нових сполук, які б проявляли діуретичну дію, мали нескладну технологію виробництва та були більш безпечними. Мета дослідження – здійснити спрямований пошук діуретиків серед невідомих дизаміщених тіосечовин і тіосемікарбазидів з використанням методології молекулярного докінгу для пояснення імовірного механізму дії. Методи дослідження. Структури цільових сполук запропоновано із застосуванням підходів “drug-design”, а саме введенням до тіосечовин і тіосемікарбазидів структурних фрагментів, характерних для відомих діуретиків. Заміщені циклоалкілкарбонілтіосечовини чи тіосемікарбазиди синтезовано однореакторним методом з використанням циклоалкілкарбонілхлоридів, амонію ізотіоціанату та заміщених анілінів або гідразидів карбонових кислот. Будову синтезованих сполук доведено методами ІЧ-, 1Н ЯМР-спектроскопії, хроматомас-спектрометрії та елементним аналізом. Спрямований пошук сполук, що впливають на видільну функцію нирок щурів, здійснено за загальноприйнятим методом Є. Б. Бєрхіна з водним навантаженням. Імовірний молекулярний механізм дії передбачено завдяки молекулярному докінгу. Результати й обговорення. Однореакторна реакція циклоалкілкарбонілхлоридів з еквімолекулярною кількістю амонію ізотіоціанату та заміщених анілінів або гідразидів карбонових кислот приводить до заміщених циклоалкілкарбонілтіосечовин чи тіосемікарбазидів. Обговорено будову синтезованих сполук з використанням даних ІЧ-, 1Н ЯМР- і хроматомас-спектрів. Дослідження впливу синтезованих сполук на видільну функцію нирок щурів при водному навантаженні дозволили виявити ряд сполук, які за діуретичною дією перевищують фуросемід та конкурують з гідрохлортіазидом. Результати молекулярного докінгу показали, що досліджувані сполуки проявляли високу спорідненість до карбоангідрази II і мали подібні сайти зв’язування з референс-препаратами. Зазначене вказує на ймовірний їх механізм дії. Висновки. Розроблена та реалізована стратегія пошуку діуретиків серед заміщених циклоалкілкарбонілтіосечовин і тіосемікарбазидів дозволила виявити ефективну сполуку (3.2), яка за силою сечогінного ефекту наближається до референс-препарату “Гідрохлортіазид”. Важливо, що, згідно з результатами молекулярного докінгу, синтезовані сполуки, як і референс-препарати, мають подібний механізм дії (інгібітори карбоангідрази II). Імовірно, виражений діуретичний ефект досліджуваних сполук пов’язаний зі здатністю заміщених тіосечовин утворювати координаційні зв’язки з катіоном цинку в активній ділянці СА II. Отримані результати обґрунтовують подальший цілеспрямований пошук потенційних діуретиків серед цього класу сполук.
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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