RESUMO
The effects of replacing the central furan ring of furamidine with indole and benzimidazole on their DNA binding affinity, antiparasitic activity and fluorescence are reported. The bis-cyanophenylindoles required to make the corresponding amidines were prepared by sequential Stille and/or Suzuki coupling reactions. The bis-cyanophenylbenzimidazoles were obtained by coupling 4-cyanobenzaldehydes with the appropriate cyano substituted phenylenediamine. The bis-nitriles were converted to the diamidines by reaction with LiN[Si(CH(3))(3)](2) or by Pinner methodology. Specifically, we have prepared new series of 2,6- and 2,5-diaryl indoles (6a,b, 12 and 17a-d) and the related benzimidazoles (24, 30 and 35). The new compounds bind in the DNA minor groove in DNA AT base pair sequences and eight of the ten new analogues exhibit ΔT(m) values comparable to or higher than that of furamidine. Six of ten of the new compounds exhibit lower IC(50) values against Trypanosoma brucei rhodesiense (T. b. r.) and eight of ten exhibit lower IC(50) values against Plasmodium falciparum (P. f.) than furamidine. Four of the ten show greater efficacy than furamidine in the rigorous T. b. r. STIB900 mouse model for African trypanosomiasis. Generally, the fluorescence properties of the new analogues are similar to that of DAPI.
Assuntos
Antiparasitários/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Benzamidinas/síntese química , Benzamidinas/farmacologia , DNA de Protozoário/efeitos dos fármacos , Animais , Antiparasitários/uso terapêutico , Antiprotozoários/química , Benzamidinas/química , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacologia , Dicroísmo Circular , Reagentes de Ligações Cruzadas/química , DNA de Protozoário/metabolismo , Fluorescência , Humanos , Camundongos , Modelos Químicos , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma brucei rhodesiense/genéticaRESUMO
A new series of 1-adamantyl derivatives was designed, synthesized and evaluated for their antimicrobial and antiviral activities. Representative derivatives of the newly synthesized compounds were tested. Ampicillin, clotimazole and the antiviral antibiotic aphidicolin were used as positive controls. Compound 18 proved to be the most active member of this series as antimicrobial against Staphylococcus aureus and Candida albicans and as antiviral with IC50 value of 0.21 mg/ml and CD50 value of 0.02 mg/ml while compound 19 proved to be the most active member of this series as antiviral with IC50 value of 0.21 mg/ml and CD50 value of 0.01 mg/ml.
