Síntese e estudo das atividades antifúngica e antitumoral dederivados acíclicos e furânicos , -bis-funcionalizados

Abstract

The present work presents the results obtained from the synthesis and the biological of several bioactive NCEs (NCE= New Chemical Entity), novel a,w-bis-functionalized molecular hybrids which were formed between: organosulfur compounds (sulphides and their correspondingsulphoxides and sulphones) functionalized with tetrazolic rings [Y(CH2)nX-(CH2)nY; Y=tetrazole; X=S,SO,SO2; n=2,3] and with hydrazides [Y(CH2)nS-(CH2)nY], Y=CONHNH2, n=1,2]; tetrahydrofurans-2,5-bis-functionalized with S-thioureido (Y=SCNRNR2, bioisosters from amidines) [YCH2X-CH2Y;Y=SCNRNR2, R=H,Me; X=2,5-THF-]. The preparation of the analogous N-alkyl-w-S-thioureido-tetrazoles was also investigated. Since, the a,w-bis-dinitriles were obtained as tetrazole precursors, the corresponding reduced amines were also prepared in orderto get a third a,w-bis-functionalized hybrid class: the organosulfur (and bioisosteric derivatives) diamino-substituted compounds coordinated with platin, another very promising and with broad pharmacological agent. It is noteworthy that all derivatives were previously planned through rational design with molecular calculations and QSAR techniques. Then, via classical and wellknown synthetic routes, 40 compounds were synthesized, among them 14 are novel. These synthesized a,w-bis-functionalized hybrids were tested against pathogenic fungi (Candida albicans, C. dubliniensis, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis; Aspergillus clavatus, A. flavus, A. niger, A. fumigatus and A. tamarii; Cryptococcus neoformans and C. gatti, Saccharomices cerevisae, Sporotrix schenkii and clinically isolates of Paracoccocidioidesbrasiliensis). The investigated tetrazole hybrids and their corresponding dinitriles showed broad action spectra against all clinically isolates from P. brasiliensis, such as against all Candida species; it is remarkable that AMB, a standard antifungal agent, is not active against P. brasiliensis; only one bis-tetrazole-sulphoxide was active against C. gatti and the tetrazolesulphones were active against C. krusei, Aspergillus clavatus e A.niger. The hydrazides, simple and easily obtaining molecules, showed activity against all species of Aspergillus, Cryptococcus and Candida, the susceptibility of C. dubliniensis, C. glabrata e C. krusei to these compounds is really remarkable since these pathogenic fungi is usually less susceptible to the common antifungal agents. The cytotoxic activity of the tetrazolic derivatives were evaluated against baby hamster kidney cells (BHK) and against some cancer cells: murine mammarian carcinoma - 4T1(M),lung adenocarcinoma- A549, human melanoma-MEWO and rat glyoma-C6. One nitrile, one bis-tetrazole-sulfide and both sulfone-tetrazoles presented activity against 4T1, and one of them at very low concentration (< 10-7 mol.L-1); it is noteworthy that these compounds showed high selectivity and low toxicity to healthy cells (BHK). The dinitriles and one of the bistetrazole-sulphide were activity against MEWO, and the latter compound was the only one active against C6; none of the studied compounds were active against A549