Synthesis of New Derivatives of Heterocyclic Systems Containing Triazolopyrimidine, thiazolo[3,2-a]pyrimidine and pyrimido[2,1-b] thiazine Moiety Showing Promising Antimicrobial Activity

Background and Objective: Continuing our research in the field of heterocyclic compounds and exploiting our experience in the synthesis of pyridothieno(furo)[3,2-d]pyrimidine derivatives decorated by suitable reactive groups (in turn able to give rise to the formation of new heterocyclic rings), we now carried out a research with the aim of building in different position of the pyrimidine some new hetero-rings: the 1,3,4-triazole, thiazole and thiazine. Moreover their possible antimicrobial activity against some gram-positive and gram-negative bacilli strains has been evaluated. Methods: Starting from the hydrazino derivative of pyrido[3',2':4,5]thieno(furo)[3,2-d]pyrimidines 2 (7) by reflux with triethyl orthoformate or formic acid, some substituted isomeric pyrido[3',2':4,5]thieno(furo)[2,3-e][1,2,4]triazolopyrimidines 3 and 4 (10) have been synthesized. By alkylation of compounds 8 with alkyl dichlorides, the cyclization to a thiazoline or to a thiazine ring on the [a] side of the pyrimidine ring occurs, with the formation of the new pentacyclic systems: pyrido[3',2':4,5]thieno[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-7(8)-one 15 and pyrido[3 '',2 '':4',5']furo(thieno)[3',2':4,5]pyrimido[2,1-b][1,3]thiazin-7(8)-ones 16. Results: 11-Alkyl(aryl)-8,8-dimethyl-7,10-dihydro-8H-pyrano[4 '',3 '':4',]pyrido[3',2':4,5]thieno[2,3-e][1,2,4] triazolo[4,3-c]pyrimidines 3 gave a Dimroth rearrangement in acidic media. It was observed that the cyclization of compounds 7 and 8 occurred linearly with the expected formation of pyrido[3',2':4,5]thieno(furo)[3,2-d][1,2,4]triazolo[4,3-a]pyrimidin-7(8)-ones 10 and pyrido[3',2':4,5]thieno[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-7(8)-one 15 and pyrido[3 '',2 '':4',5']furo(thieno)[3',2':4,5]pyrimido[2,1-b][1,3]thiazin-7(8)-ones 16: that is triazole, thiazole and thiazine ring condensation occurs at the [b] side of the pyrimidine ring. During the alkylation of compounds 7, the unusual cleavage of the hydrazino group took place with the formation of 8(9)-methylpyrido[3',2':4,5]thieno(furo)[3,2-d]pyrimidin-7(8)-ones 12. Conclusion: The synthesis of some new 'complex' pentaheterocyclic systems containing triazolopyrimidine, thiazolo[3,2-a]pyrimidine and pyrimido[2,1-b]thiazine moiety based on the pyrido[3',2':4,5]thieno(furo)[3,2-d]pyrimidines is described. During the alkylation of 9(10)-hydrazinopyrido[3',2':4,5]thieno(furo)[3,2-d]pyrimidin-7(8)-ones 7 an unexpected cleavage of the hydrazino group has been observed with the formation of 8(9)-methylpyrido[3',2':4,5]thieno(furo)[3,2-d]pyrimidin-7(8)-ones 12. Biological tests on the newly synthesized compounds evidenced that some of them showed promising antimicrobial activity.