α(β)-Cульфоніл(фосфорил)акрилонітрили та енаміни в синтезі біоактивних гетероциклів

Functionalization of heterocyclic systems with sulfur- and phosphorus-containing pharmacophores has long shown itself as an effective method for construction of new bioactive substances. At the same time, some types of the compounds are represented by only a few examples, and it prevents further evaluation of the contribution of certain structural elements to biological effects of the sulfonyl- and phosphoryl-substituted heterocyclic derivatives studied. Therefore, a relevant task for organic and medicinal chemistry still remains development of new methods for the synthesis of heterocyclic compounds with sulfonyl and phosphoryl groups, as well as determination of the biological activity of these substances. A structural variety of sulfonyl- and phosphoryl-substituted heterocycles can be achieved by using heterofunctional low-molecular compounds with sulfonyl and phosphoryl groups. This review highlights the information on biologically active heterocyclic compounds synthesized from acrylonitriles and enamines of sulfones, phosphine oxides, and phosphonates series.Received: 05.02.2020Revised: 25.05.2020Accepted: 27.08.2020Функціоналізація гетероциклічних систем фармакофорними сульфуро- та фосфоровмісними угрупуваннями давно зарекомендувала себе як ефективний метод створення нових лікарських засобів. Разом із тим, деякі з типів структур представлено лише поодинокими прикладами, що не дозволяє оцінити внесок певних структурних елементів у прояв біологічної дії досліджуваних сульфоніл- та фосфорилзаміщених гетероциклічних сполук. Тому розробка нових методів синтезу гетероциклічних сполук із сульфонільними та фосфорильними групами, а також встановлення біологічної активності таких продуктів досі залишаються актуальним завданням для органічної та медичної хімії. Широку варіативність у синтезі сульфоніл- та фосфорилзаміщених гетероциклів можуть забезпечити низькомолекулярні поліфункціональні речовини із сульфонільними та фосфорильними групами. У цьому огляді висвітлено наявну інформацію стосовно біологічно активних гетероциклічних сполук, які були синтезовані на основі акрилонітрилів та енамінів ряду сульфонів, фосфіноксидів та фосфонатів.Received: 05.02.2020 Revised: 25.05.2020 Accepted: 27.08.202

Synthesis of fused heterocycles from 2-aryl-5-(chlorosulfonyl)-1,3-oxazole-4-carboxylates and α-aminoazoles involving the Smiles rearrangement

Reaction of methyl 2-aryl-5-(chlorosulfonyl)-1,3-oxazole-4-carboxylates with 1H-pyrazol-5-amines and 1H-1,2,4-triazol-5-amines proceeds with the participation of endocyclic aminoazole nitrogen atoms to yield products containing a primary amino group. Being treated by sodium hydride these products undergo a further transformation into the tricyclic compounds. It has been shown that the cyclocondensation pathway includes the Smiles rearrangement with extrusion of SO2 followed by the elimination of MeOH. This reaction sequence is a convenient approach to the synthesis of new annulated [1,3]oxazolo[5,4-d]pyrimidine derivatives

Ітеративне використання великих хімічних просторів у пошуку лікарських засобів

Aim. To demonstrate the advantages of large-scale virtual libraries generated using chemical protocols previously validated in primary steps of the drug discovery process.Results and discussion. Two validated parallel chemistry protocols reported earlier were used to create the chemical space. It was then sampled based on diversity metric, and the sample was subjected to the virtual screening on BRD4 target. Hits of virtual screening were synthesized and tested in the thermal shift assay.Experimental part. The chemical space was generated using commercially available building blocks and synthetic protocols suitable for parallel chemistry and previously reported. After narrowing it down, using MedChem filters, the resulting sub-space was clustered based on diversity metrics. Centroids of the clusters were put to the virtual screening against the BRD4 active center. 29 Hits from the docking were synthesized and subjected to the thermal shift assay with BRD4, and 2 compounds showed noticeable dTm.Conclusions. A combination of cheminformatics and molecular docking was applied to find novel potential binders for BRD4 from a large chemical space. The selected set of predicted molecules was synthesized with a 72 % success rate and tested in a thermal shift assay to reveal a 6 % hit rate. The selection can be performed iteratively to fast support of the drug discovery.Мета. Продемонструвати переваги віртуальних бібліотек великого розміру, згенерованих за валідованими раніше хімічними протоколами, на перших етапах пошуку лікарських засобів.Результати та їх обговорення. На основі двох валідованих методів синтезу, придатних для паралельної хімії, описаних раніше, було створено хімічний простір. На основі різноманітності з одержаної віртуальної бібліотеки зроблено вибірку, яку було піддано віртуальному скринінгу щодо активного центру білка BRD4. Хіти віртуального скринінгу було синтезовано й перевірено за допомогою диференційної сканувальної калориметрії.Експериментальна частина. На основі комерційно доступних вихідних реагентів та раніше репрезентованих синтетичних протоколів, придатних для паралельної хімії, згенеровано хімічний простір. Простір було зменшено за рахунок застосування медхімічних фільтрів; результатний підпростір було кластеризовано за критерієм різноманітності. Центроїди кластерів було піддано молекулярному докінгу щодо активного центру білка BRD4. Базуючись на результатах проведеного докінгу, синтезовано 29 хітів, які було піддано диференційній сканувальній калориметрії з білком BRD4; з цим 2 сполуки продемонстрували помітний зсув точки топлення.Висновки. Для пошуку нових потенційних лігандів BRD4 у великому хімічному просторі було застосовано комбінацію хемоінформатики і молекулярного докінгу. Набір молекул, що мали високу передбачену активність, було синтезовано з успішністю 72 %. Серед синтезованих сполук виявлено первинні хіти (6 % сполук). Подібний процес можна повторювати ітеративно для швидкої підтримки розроблення ліків

Lithiation of 2-bromo-4-(1,3-dioxolan-2-yl)-1,3-thiazole

The reaction of lithiation of 2-bromo-4-(1,3-dioxolan-2-yl)-1,3-thiazole with in position 5 of the thiazole ring and double lithiation with t-butyllithium (t-BuLi) in positions 2 and 5 lithium diisopropylamide (LDA) are investigated. When lithiated and dilithiated thiazoles were treated with different electrophiles, a number of trifunctional 1,3-thiazoles were obtained with high yields

Regioselective synthesis of bicyclic 1,3,5-triazepine system starting from tetrachloro-2-aza-1,3-butadienes

Readily available tetrachloro-2-aza-1,3-butadienes enter into directed cyclocondensation reaction with N-phenyl-1,2-cyclopentanediamine which leads to regioselective cyclopentane annulation by the 1,3,5-triazepine. The formation of the 1,3,5-triazepine derivatives was confirmed proved by 1H- and 13C-NMR spectral study, elemental analysis and, in one case, single-crystal x-ray crystallographic study

In silico study of 4-phosphorylated derivatives of 1,3-oxazole as inhibitors of Candida albicans fructose-1,6-bisphosphate aldolase II

In this study, the synthesis, in vitro anti-Candida activity and molecular modeling of 4-phosphorylated derivatives of 1,3-oxazole as inhibitors of Candida albicans fructose-1,6-bisphosphate aldolase (FBA-II) are demonstrated and discussed. Significant similarity of the primary and secondary structure, binding sites and active sites of FBA-II C. albicans and Mycobacterium tuberculosis are established. FBA-II C. albicans inhibitors contained 1,3-oxazole-4-phosphonates moiety are created by analogy to inhibitors FBA-II M. tuberculosis. The experimental studies of the anti-Candida activity of the designed and synthesized compounds have shown their high activity against standard strain and its C. albicans fluconazole resistant clinical isolate. It was hypothesized that the growth suppression of fluconazole-resistant С. albicans strain may be due to the inhibition of aldolase fructose-1,6-bisphosphate. A qualitative homology 3D model of the C. albicans FBA-II was created using SWISS-MODEL server. The probable mechanism of FBA-II inhibition by studied 4-phosphorylated derivatives was shown using molecular docking. The main role of amino acid residues His110, His226, Gly227, Leu248, Val238, Asp144, Lys230, Glu147, Gly227, Ala112, Leu145 and catalytic zinc atom in the formation of stable ligand-protein complexes with ΔG = –6.89, –7.2, –7.16, –7.5, –8.0, –7.9 kcal/mol was shown.Thus, the positive results obtained in the work were demonstrated the promise of using the proposed homology 3D model of the C. albicans FBA-II as the target for the search and development of new anti-Candida agents against azole-resistant fungal pathogens. Designed and studied 4-phosphorylated derivatives of 1,3-oxazole having a direct inhibiting FBA-II molecular mechanism of action can be used as perspective drug-candidates against resistant C. albicans strains

Theoretical and Experimental Studies of Phosphonium Ionic Liquids as Potential Antibacterials of MDR <i>Acinetobacter baumannii</i>

A previously developed model to predict antibacterial activity of ionic liquids against a resistant A. baumannii strain was used to assess activity of phosphonium ionic liquids. Their antioxidant potential was additionally evaluated with newly developed models, which were based on public data. The accuracy of the models was rigorously evaluated using cross-validation as well as test set prediction. Six alkyl triphenylphosphonium and alkyl tributylphosphonium bromides with the C8, C10, and C12 alkyl chain length were synthesized and tested in vitro. Experimental studies confirmed their activity against A. baumannii as well as showed pronounced antioxidant properties. These results suggest that phosphonium ionic liquids could be promising lead structures against A. baumannii

Theoretical and Experimental Studies of Phosphonium Ionic Liquids as Potential Antibacterials of MDR Acinetobacter baumannii

A previously developed model to predict antibacterial activity of ionic liquids against a resistant A. baumannii strain was used to assess activity of phosphonium ionic liquids. Their antioxidant potential was additionally evaluated with newly developed models, which were based on public data. The accuracy of the models was rigorously evaluated using cross-validation as well as test set prediction. Six alkyl triphenylphosphonium and alkyl tributylphosphonium bromides with the C8, C10, and C12 alkyl chain length were synthesized and tested in vitro. Experimental studies confirmed their activity against A. baumannii as well as showed pronounced antioxidant properties. These results suggest that phosphonium ionic liquids could be promising lead structures against A. baumannii

Facile One-Pot Parallel Synthesis of 3‑Amino-1,2,4-triazoles

A 1,2,4-triazole motif is present in numerous commercialized and investigational bioactive molecules. Despite its importance for medicinal chemistry, there is a lack of convenient combinatorial approaches toward this molecular core. Herein, we present a synthetic strategy suitable for the quick preparation of a library of structurally diverse 1,2,4-triazoles in a one-pot setting. The key steps include the formation of thioureas followed by <i>S</i>-alkylation using 1,3-propane sultone and consecutive ring closure leading to the desired 1,2,4-triazoles. Parallel synthesis yields thousands of 1,2,4-triazoles in a cost- and time-efficient manner from commercially available chemicals