SYNTHESIS OF SELECTED FUNCTIONALIZED DERIVATIVES OF THIAZOLO[3,2-b][1,2,4]TRIAZOLE, IMIDAZO[2,1-b]THIAZOLE AND IMIDAZO[2,1-b][1,3,4]THIADIAZOLE

N. Pokhodylo


DOI: http://dx.doi.org/10.30970/vch.6401.255

Abstract


Functionalized thiazolo[3,2-b][1,2,4]triazole, imidazo[2,1-b]thiazole, and imidazo[2,1-b] [1,3,4]thiadiazole derivatives are critical building blocks for medical chemistry. Their potential has, however, only become the object of research relatively recently. This is due to the fact that the introduction of these condensed systems, consisting of five-membered heterocyclic nuclei, into compounds induces the manifestation of various biological effects. Nevertheless, many representatives of these heterocyclic compounds are still difficult to obtain due to a number of synthetic limitations associated with the lability of a number of their derivatives.

In such regard, alkyl derivatives of thiazolo[2,3-c][1,2,4]triazole-6-carboxylic acids were synthesized. The advantage of the method is that the substituent in the third position is introduced during the main closure of 1,2,4-triazolazole from the corresponding acylthiosemicazide, which allows for a wide variety of substituents. Thus, available 2-acetyl- and 2-isobutyrylhydrazine-1-carbothioamides 1a,b were cyclized under the action of sodium methylate to 5-methyl- and5-isopropyl-4H-1,2,4-triazole-3-thiols 2a,b. During the alkylation of thiols 2a,b with 2-chloroacetoacetic ester, salts 4a,b were obtained, which during intramolecular cyclization under the action of a dehydrating agent – sulfuric acid – formed ethyl 3-methyl/isopropyl-5-methylthiazolo[2,3-с][1,2, 4]triazole-6-carboxylates 5a,b, which upon mild hydrolysis give the target acids 6. The obtained acids 6a,b are stable, which allows us to consider them as building blocks for the creation of biological molecules.

Among bioisosteric to thiazolo[3,2-b][1,2,4]triazolo ring, there are no data on imidazo[2,1-b][1,3,4]thiadiazole-5-carboxylic acids. Attempts were made to obtain 6-methylimidazo[2,1-b][1,3,4]thiadiazole-5-carboxylic acid by two parallel approaches based on the available starting reagents. In particular, cyclization of 1,3,4-thiadiazol-2-amine 7 with ethyl and benzene esters of 2-chloroacetoacetic acid gave esters 8a,b. However, attempts to hydrolyze the ethyl ester or remove benzyl protection under catalytic hydrogenation were unsuccessful.

Taking into account the practical value of the building blocks of imidazolylthia(di)azole series, the synthesis of imidazo[2,1-b]thiazole-6-carboxylic acid derivatives 15 was carried out. For this purpose, the synthesis route was chosen to widely vary the substituents in the thiazole ring. The imizole fragment was formed from glycine ethyl ester hydrochloride 10 by sequential N- and C-acelation of ethyl formate with the formation of a disodium salt 11, which under the action of potassium thiocyanate is cyclized to form the original ethyl 2-mercapto-1H-imidazole-5-carboxylate 12. After alkylation of sulphur with α-bromoketones, the obtained intermediate thioketones easily undergo intramolecular cyclization with the thiazole ring annulation and the formation of ethyl 3-aryl-imidazo[2,1-b]thiazole-6-carboxylates 15a,b. As a way of their possible application, the reduction of the ester groups to alcohols 16 ware carried out, which is promising for further conjugations into biomolecules.

In conclusion, convenient synthetic methods for the synthesis of some functionalized derivatives of thiazolo[3,2-b][1,2,4]triazole, imidazo[2,1-b]thiazole and imidazo[2,1-b] [1,3,4]thiadiazole were developed. In particular, 2-alkyl-6-methylthiazolo[3,2-b][1,2,4]triazole-5-carboxylic acids, imidazo[2,1-b]thiazole-6-carboxylates and (imidazo[2,1 -b]thiazol-6-yl)methanols are useful for their use as building blocks for constructing molecules to discover biological activity.

 

Keywords: thiazolo[3,2-b][1,2,4]triazoles, imidazo[2,1-b]thiazoles, imidazo[2,1-b] [1,3,4]thiadiazoles, cyclization.


References


Bhongade B. A., Talath S., Gadad R. A. et al. Biological activities of imidazo[2,1-b][1,3,4]thiadiazole derivatives: A review // J. Saudi Chem. Soc. 2016. Vol. 20. P. 463−475. DOI: https://doi.org/10.1016/j.jscs.2013.01.010

Grygorenko O. O., Volochnyuk D. M., Vashchenko B. V. Emerging building blocks for medicinal chemistry: Recent synthetic advances // Eur. J. Org. Chem., 2021. Vol. 2021, Iss. 47. P. 6478−6510. DOI: https://doi.org/10.1002/ejoc.202100857

Liu S. et al. Preparation of the 6-methyl-thiazole-5-carboxamide derivative and application as vascular endothelial growth factor receptor tyrosine kinase inhibitor CN107445979 https://patents.google.com/patent/CN107445979A/en?oq=CN107445979

Toma A., Mogoşan C., Vlase L. et al. Heterocycles 39. Synthesis, characterization and evaluation of the anti-inflammatory activity of thiazolo[3,2-b][1,2,4]triazole derivatives bearing pyridin-3/4-yl moiety // Med. Chem. Res. 2017. Vol. 26, Iss. 10. P. 2602−2613. DOI: https://doi.org/10.1007/s00044-017-1959-x

Tozkoparan B., Aytaç S. P., Gürsoy Ş. et al. Design and synthesis of some thiazolotriazolyl esters as anti-inflammatory and analgesic agents // Med. Chem. Res. 2012. Vol. 21, Iss. 2. P. 192−201. DOI: https://doi.org/10.1007/s00044-010-9508-x

Zaharia V., Silvestru A., Palibroda N. et al. Heterocycles 28. Synthesis and characterization of some bis and polyhetererocyclic compounds with anti-inflammatory potential // Farmacia. 2011. Vol. 59. P. 624−635. https://farmaciajournal.com/arhiva/20115/art.3.zaharia%20624-635.pdf

Janowska S., Paneth A. Wujec M. Cytotoxic properties of 1, 3, 4-thiadiazole derivatives – A review // Molecules. 2020. Vol. 25, Iss. 18. Art. 4309. DOI: https://doi.org/10.3390/molecules25184309

Terzioglu N., Gürsoy A. Synthesis and anticancer evaluation of some new hydrazone derivatives of 2,6-dimethylimidazo[2,1-b][1,3,4]thiadiazole-5-carbohydrazide // Eur. J. Med. Chem. 2003. Vol. 38, Iss. 7−8. P. 781−786. DOI: https://doi.org/10.1016/S0223-5234(03)00138-7

Atta K. F., Farahat O. O., Ahmed A. Z. et al. Synthesis and antibacterial activities of novel imidazo[2,1-b]-1,3,4-thiadiazoles // Molecules. 2011. Vol. 16, Iss. 7. P. 5496−5506. DOI: https://doi.org/10.3390/molecules16075496

Yan Guo F., Ji Zheng C., Wang M. et al. Synthesis and antimicrobial activity evaluation of imidazole-fused imidazo[2,1-b][1,3,4]thiadiazole analogues // Chem. Med. Chem. 2021. Vol. 16, Iss. 15. P. 2354−2365. DOI: https://doi.org/10.1002/cmdc.202100122

Ramprasad J., Nayak N., Dalimba U. et al. One-pot synthesis of new triazole—Imidazo[2,1-b][1,3,4]thiadiazole hybrids via click chemistry and evaluation of their antitubercular activity // Bioorg. Med. Chem. Lett. 2015. Vol. 25, Iss. 19. P. 4169−4173. DOI: https://doi.org/10.1016/j.bmcl.2015.08.009

Cristina A., Leonte D., Vlase L. et al. Heterocycles 48. Synthesis, characterization and biological evaluation of imidazo[2,1-b][1,3,4]thiadiazole derivatives as anti-inflammatory agents // Molecules. 2018. Vol. 23, Iss. 10. Art. 2425. DOI: https://doi.org/10.3390/molecules23102425

Azimi S., Firuzi O., Iraji A., et al. Synthesis and in vitro biological activity evaluation of novel imidazo [2,1-b][1,3,4]thiadiazole as anti-alzheimer agents // Lett. Drug Des. Discov. 2020. Vol. 17, Iss. 5. P. 610−617. DOI: https://doi.org/10.2174/1570180816666181108115510

Shareef M. A., Khan I., Babu B. N. et al. A comprehensive review on the therapeutic versatility of imidazo[2,1-b]thiazoles // Curr. Med. Chem. 2020. Vol. 27, Iss. 40. P. 6864−6887.DOI: https://doi.org/10.2174/0929867326666190729152440

Sbenati R. M., Semreen M. H., Semreen A. M., et al. Evaluation of imidazo[2,1–b]thiazole-based anticancer agents in one decade (2011–2020): Current status and future prospects // Bioorg. Med. Chem. 2021. Vol. 29. Art. 115897. DOI: https://doi.org/10.1016/j.bmc.2020.115897

Leoni A., Frosini M., Locatelli A. et al. 4-Imidazo [2, 1-b] thiazole-1, 4-DHPs and neuroprotection: preliminary study in hits searching // Eur. J. Med. Chem., 2019. Vol. 2019. Iss. 169. P. 89−102. DOI: https://doi.org/10.1016/j.ejmech.2019.02.075

Moraski G. C., Seeger N., Miller P. A. et al. Arrival of imidazo[2,1-b]thiazole-5-carboxamides: potent anti-tuberculosis agents that target QcrB. ACS Infect. Dis. 2016. Vol. 2, Iss. 6. P. 393−398. DOI: https://doi.org/10.1021/acsinfecdis.5b00154

Wang N. Y., Xu Y., Zuo W. Q. et al. Discovery of imidazo[2,1-b]thiazole HCV NS4B inhibitors exhibiting synergistic effect with other direct-acting antiviral agents // J. Med. Chem. 2015. Vol. 58, Iss. 6. P. 2764−2778. DOI: https://doi.org/10.1021/jm501934n

Shyyka О., Pokhodylo N., Obushak M. Synthesis of new heterocyclic system thiazolo[3,2-a]thieno[2,3-d]imidazole. // Visnyk Lviv Univ. Ser. Chem. 2015. Iss. 56, Part. 2. P. 237–242.

Ibrahim M. K. A., Elghandour A. H., Abou-hadeed K. Reactions with heterocyclic diazonium salts: synthesis of several new thiazolo[2,3-c]as-triazines and thiazolo[2,3-c]-1,2,4-triazole derivatives // Phosphorus Sulfur Silicon Relat. Elem. 1991. Vol. 60, Iss. 1−2. P. 119−123. DOI: https://doi.org/10.1080/10426509108233932

Abdelhamid A. O., Afifi M. A. Reactions of hydrazidoyl halides: Synthesis of imidazo[2,1-b]thiazole, thiazolo[2,3-c]-as-triazole and heterocyclic enaminonitriles. Phosphorus Sulfur Silicon Relat. Elem. 1988. Vol. 36, Iss. 1−2. P. 129−133. DOI: https://doi.org/10.1080/03086648808079007

Simiti I., Zaharia V., Coman M. et al. Heterocyclen, 65. Mitt.: Darstellung und chemisches Verhalten einiger 2−Aryl−6−ethoxycarbonyl−5−methyl−thiazolo[3,2−b] −1,2,4−triazole // Arch. Pharm. 1991. Vol. 324, Iss. 1. P. 49−51. DOI: https://doi.org/10.1002/ardp.19913240113


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