Репозитарій

Nowadays the discovery of effective antioxidant agents among low-molecular-weight organic molecules is a recent problem that requires new methodological approaches implementation, while it is also the society relevant task [1]. Both thiazole and pyridine scaffolds are of the highest priority in modern medicinal chemistry [2, 3]. Numerous reports concerning variety biological effects possessed by thiazolopyridine derivatives have been currently published including their discovery as potent antioxidant agents [4].

One of the antioxidant action mechanisms can be exerted through the inhibition enzymes’ activity which are responsible for reactive oxygen species (ROS) producing, thereby reducing oxidative stress. The objective of the precent study was to fulfil molecular docking studies of novel 3H-thiazolo[4,5-b]pyridine-2-one derivatives towards lipoxygenase (LOX) as one of ROS-producing enzymes. LOX-5 is the enzyme that catalyses the oxidation of polyunsaturated fatty acids to form lipid hydroperoxides, which can lead to membrane damage and inflammation.

The objects of the precent research were three series of condensed 3H-thiazolo[4,5-b]pyridine derivatives, synthesized at Danylo Halytsky Lviv National Medical University [5-7]: (a) the 1^st series included N³ substituted derivatives containing phenyl, propanenitrile, propanoic acid and phenylpropanamide moieties as N³-substituents while they comprised hydroxyl group at C⁵ position; (b) the 2^nd series comprised compounds incorporated substituted phenyl diazonium or alkyl substituents at C⁶ position of the core scaffold; (c) the 3^rd series included derivatives incorporated chloroacetate, chlorobenzoate, benzyloxybenzoate, methoxyphenyl acrylate and substituted phenyltriazolecarboxylate moieties as the substituents at C⁵ position of the core scaffold (Fig. 1). The antioxidant activity evaluation of all tested compounds was reported as a spectrophotometric DPPH assay based on the ability of antioxidant drug candidates possess free radical scavenging potency. Compounds of all three series were found to exhibit moderate and low antioxidant effects.

Probing the action mechanism of 3H-thiazolo[4,5-b]pyridin-2-one derivatives as antioxidants was performed through molecular docking studies towards lipoxygenase. Docking studies, filtering and poses grouping according to the Estimated Affinity towards the biotarget were carried out using SeeSar13.1.0 software (BioSolveIT, Sankt Augustin, Germany) [8]. The crystal structures of lipoxygenase were downloaded from Protein Data Bank using the Protein Mode of the software. Two structures of LOX-5 were downloaded: PDB entry 3O8Y - a 2.39 Å resolution structure of LOX-5 without ligands; PDB entry 6N2W – a 2.71 Å resolution structure of LOX-5 with co-crystallized ligand NDGA (Masoprocol, 4-[(2r,3s)-3-[(3,4-dihydroxyphenyl)methyl]-2-methylbutyl]benzene-1,2-diol).

Actuality. Discovery of innovative drug candidates is one of the relevant tasks of modern medical and pharmaceutical science. The thiazole core is a versatile scaffold for the development of new drugs and biologically active agents [1]. The recent publications, dealing with synthesis and pharmacological screening of thiazole-bearing heterocycles and their activity mechanisms [2-4], indicate the relevance of further drug discovery among novel derivatives of the specified chemical class.

The objectives. The precent work is devoted to the systematic study and generalization of the main trends in the field of potential antimicrobial drug candidates development of among condensed thiazolo[4,5-b]pyridine derivatives.

Materials and methods. The complex of general scientific methods of searching and systematizing literary references, analysis and comparison of information from various sources was used, followed by generalization of new and promising directions.

Results. Thiazolo[4,5-b]pyridine derivatives have been extensively evaluated as antimicrobial agents. Abd El-Mahmoud reported antimicrobial and antifungal screening for 5-amino-2-thioxo-2,3,4,7-tetrahydro-1,3-thiazolo-[4,5-b]pyridine-6-carbonitriles [5]. All compounds showed moderate antimicrobial activity against Staphylococcus aureus (St). Some compounds from this series showed moderate antimicrobial activity against Bacillus subtilis (B.C.) and Proteus vulgaris (P. vulgaris). The lead compound was highly active against Aspergillus flavus (A. flavus).

El-Sofany et al.reported in vitro antimicrobial and antifungal activity evaluation of novel spiro[cyclohexane-1,2'-thiazolo[4,5-b]pyridine derivatives [6]. SAR analysis revealed that open-chain sugar moieties introduction played a significant role in antimicrobial activity increasing. It was also shown that acetylated aldoses were less active than non-acylated ones and the activity increased by increasing the number of -OH groups rather than -OAc groups in the open-chain sugar nucleus.

Lozynsky et al. reported antimicrobial activity in vitro evaluation for 5,7-substituted 3H-thiazolo[4,5-b]pyridin-2-ones [7]. It was shown that the antibacterial effect did not depend on the substituents at C⁵ and C⁷ positions. The presence of amide fragment was favorable for antimicrobial potency.

Conclusions. The current trends in discovery of new active pharmaceutical ingredients among condensed thiazolo[4,5-b]pyridine derivatives exhibiting antimicrobial activity was based on structural modification strategy of the core condensed scaffold at C², C⁵, C⁶, and C⁷ positions followed by pharmacological screening.

Acknowledgement: O. K. thanks Universidad San Pablo CEU for a Postdoctoral Contract for Ukrainian Researchers 2022-2024.

Actuality. The development of anti-inflammatory drugs occupies an important role in the field of modern pharmacology. Cyclooxygenases (COX-1 and COX-2) are the key enzymes involved in the arachidonic acid cascade. Classical non-steroidal anti-inflammatory drugs (NSAIDs) are diverse group of compounds used for the treatment of inflammation exerting their anti-inflammatory, analgesic, and antipyretic effects through the non-selective inhibition of both COX isoforms. In the past decade fused thiazole-based derivatives became an integral part of new anti-inflammatory agents’ discovery. A wide range of synthetic thiazole-bearing derivatives have been studied for their anti-inflammatory properties including COX-1/COX-2 inhibitory action [1].

The objectives. Introduction of molecular modeling methods within the computer-aided drug discovery process allows to minimize the time and costs for construction and development of new biologically active substances and may accelerate and facilitate the identification of novel COX-1/2 inhibitors among fused thiazole-scaffold bearing compounds.

Materials and methods. The objects of the precent research were three series of 37 N³, C⁵ and C⁶ substituted 3H-thiazolo[4,5-b]pyridine-2-one derivatives, synthesized at Danylo Halytsky Lviv National Medical University.  Probing the action mechanism of thiazolopyridines as anti-exudative agents was performed through molecular docking studies towards COX1/2. Docking, filtering and poses grouping according to the Estimated Affinity were carried out using SeeSar13.1.0 software [2].

Results. The structures of COX-1 in complex with Celecoxib (PDB entry 3KK6) and human COX-2 in complex with Rofecoxib (PDB entry 3KK6) were downloaded from Protein Data Bank. Co-crystalized ligands were extracted from the binding sites. Docking of the set of 37 ligands, Mefenamic acid and Ibuprofen as references were carried out utilizing two workflows: Standard docking and Template Docking. Visual inspection of poses and their Lipophilic Ligand efficiency (LLE) evaluation led us to choose Template docking outcomes with Ibuprofen as the template for further analysis. All poses were checked and transferred to the Analyzer Mode. Molecules were grouped by the pose of each compound with the best estimated activity. The analysis of docking results against COX-1 allowed to conclude, that all docked ligands had the proper orientation in the binding site of COX-1, most common amino acid residues of the protein for hydrogen binding with ligands were ARG-120 and SER-530, the HYDE scores of the most active ligands exceed that ones for Celecoxib.

  Docking results against COX-2 revealed that hydrogen bonds in most ligand-receptor complexes were formed between Oxygen atom of thiazole ring and TYR-355 amino acid residue. Favourable HYDE scores corresponded to Sulfur atom of thiazole ring and/or C³ and C⁵ carbons of phenyl substituent in N³ position of fused scaffold contributions. Non-favorable contributions referred to Oxygen atom of thiazole ring. At the same time, in both docking procedures for the ligands under study their Estimated Affinity towards COX-2 was significantly lower than that one for Ibuprofen despite they were able to achieve proper orientations.

Conclusions. The number of hit compounds under study showed high Estimated Affinity, proper binding orientation and significant HYDE scores towards proposed protein targets. However, no exact correlation between experimental pharmacological activities and docking scores was found.

Acknowledgement: O. K. thanks Universidad San Pablo CEU for a Postdoctoral Contract for Ukrainian Researchers 2022-2024.

Introduction. Nitrogen-based heterocycles are an extremely important class of organic substances widely used in medicinal chemistry, since more than 60% of drugs and more than 85% of biologically active substances described in the literature contain a Nitrogen-containing heterocycle in their structure. The оbjective of thе prеsent study wаs to synthеsize sоme nоvel antiоxidant аgеnts viа a structurаl mоdification оf еarly оbtainеd 3-(5-mercapto-[1,3,4]oxodiazole-2-yl-methyl)-5,7-dimethyl-3H-thiazolo[4,5-b]pyridine-2-one fоr furthеr pharmаcological scrеening in vitrо as antiоxidants.

Results and discussion. For broadening the scope of mercapto substituteds thiazolo[4,5-b]pyridines, we involved 3-(5-mercapto-[1,3,4]oxodiazole-2-yl-methyl)-5,7-dimethyl-3H-thiazolo[4,5-b]pyridine-2-one into cynoethylation reaction taking the advantage of the good leaving hydrogen atom property of the SH-group. It is established that the most optimal conditions for the introduction of the β-cyanoethyl fragment on the base scaffold thiol group consists of the interaction of 3-(5-mercapto-[1,3,4]oxodiazol-2-yl-methyl)-5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-2-one with acrylonitrile in a pyridine-water medium at a ratio of 5:1, this made it possible to obtain the corresponding 3-[5-(5,7-dimethyl-2-oxothiazolo[4,5-b]pyridin-3-ylmethyl)-[1,3,4]oxodiazol-2-ylsulfanyl-propionitrile. Obtained through the mentioned above reaction compound was subjected to hydrolysis leading to 3-(5-hydroxy-7-methyl-2-oxothiazolo[4,5-b]pyridin-3(2H)-yl) propanoic acid formation. For carboxyl group transformation, the corresponding chloranhydride, which belongs to unstable highly reactive reagents was obtained, so its application in further transformations was carried out without isolation by introducing aromatic amines acylation. The above conversion allowed to obtain a number of suitable propionamides. The antioxidant activity of the synthesized compounds was measured in vitro by the method of scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals. The present results of аntioxidant  activity have shown that the synthesized compounds demonstrated considerable аntioxidant  effects. Further optimization of the structure to improve biological activity is currently in progress. Conclusions. A sеries of thiazоlo[4,5-b]pyridinе-2-ones pоssessing аntioxidant аctivities wеre preparеd by the structurаl mоdification of thе cоre heterоcycle. Whеn cоmpared with еxisting аntioxidants, some оur cоmpounds wеre fоund to bе mоre potеnt. Thus the cоre fused heterocyclе mаy be cоnsidered as a prоmising scаffold for аntioxidant drug cаndidates devеlopment.

Вступ. Похідні гетероциклічних скафолдів належать до групи сполук із доведеною значимістю у сучасній медичній хімії. З-поміж азотовмісних гетероциклів у сучасному дизайні лікарських засобів чільне місце посідають тіазольний та піридиновий цикли, що є ідеальними фармакофорними ядрами та універсальними скафолдами для розробки нових біологічно активних речовин.

Матеріали та методи. Дана робота присвячена систематичному вивченню та узагальненню основних тенденцій у галузі розробки потенційних протипухлинних лікарських засобів серед конденсованих похідних на основі тіазоло[4,5-b]піридину з використанням комплексу загальнонаукових методів пошуку, аналізу та систематизації інформації з різних джерел.

Результати та обговорення. Протягом останнього десятиріччя було опубліковано низку результатів досліджень нових похідних тіазоло[4,5-b]піридину як потенційних протипухлинних засобів. Зокрема, було проведено синтез та фармакологічний скринінг 4-([4,5-b]піридин-2-іл)аміно)бензолсульфонаміду та  його похідних, що виявили подвійну антимікробну та протиракову дію.¹ Природа замісника у положенні C⁵ піридинового циклу мала вирішальне значення для посилення обох видів активності. Також цитотоксичну активність було визначено для ряду нових C⁵, C⁶ і N³ заміщених похідних 3H-тіазоло[4,5-b]піридин-2-ону,  що містили гідроксильну групу, метильний, естеріаліфатичні або естеріароматичні фрагменти в положенні С⁵ та/або алкільні, бензильні, фенілазо та іл-азобензолсульфонамідні фрагменти в положенні С⁶ базового скафолду.² Досліджувані сполуки проявили помітну протипухлинну активність, головним чином проти раку головного мозку і хребта, раку молочної залози, раку легенів та лейкемії. Стратегію раціонального дизайну було застосовано для синтезу 5-аміно-6-ізоціано-7-(тіофен-2-іл)тіазоло[4,5-b]піридин-2(3Н)-тіону на основі біоізостеричної модифікації та оптимізації структури росковітину.³ Отримана сполука продемонструвала високу in vitro цитотоксичність відносно клітинної лінії HCT-116 раку товстої кишки людини.

Висновки. Дизайн нових активних фармацевтичних інгредієнтів на основі конденсованого тіазоло[4,5-b]піридинового скафолду, що проявляють протипухлинну активність, базувався на  використанні стратегії структурних модифікацій базового конденсованого скафолда за положеннями N³, C⁵, C⁶ і C⁷ з подальшим фармакологічним або in silico скринінгом. 

Подяка: Олена Кленіна вдячна Universidad San Pablo CEU за постдокторську позицію для українських дослідників на 2022-2024 рр.