RESUMO
Polyamides-based compounds related to the Streptomycetal distamycin and netropsin are potent cytostatic molecules that bind to AT-rich regions of the minor groove of the DNA, hence interfering with DNA replication and transcription. Recently, derivatives belonging to this scaffold have been reported to halt the proliferation of deadly African trypanosomes by different and unrelated mechanisms. Here we describe the synthesis and preliminary characterization of the anti-trypanosomal mode of action of new potent and selective distamycin analogues. Two tri-heterocyclic derivatives containing a central N-methyl pyrrole ring (16 and 17) displayed high activity (EC50 < 20 nM) and selectivity (selectivity index >5000 with respect to mammalian macrophages) against the infective form of T. brucei. Both compounds caused cell cycle arrest by blocking the replication of the mitochondrial DNA but without affecting its integrity. This mode of action clearly differs from that reported for classical minor groove binder (MGB) drugs, which induce the degradation of the mitochondrial DNA. In line with this, in vitro assays suggest that 16 and 17 have a comparatively lower affinity for different template DNAs than the MGB drug diminazene. Therapeutic efficacy studies and stability assays suggest that the pharmacological properties of the hits should be optimized. The compounds can be rated as excellent scaffolds for the design of highly potent and selective anti-T. brucei agents.
Assuntos
Ciclo Celular/efeitos dos fármacos , Distamicinas/química , Macrófagos/efeitos dos fármacos , Tiazóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Animais , Feminino , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Tiazóis/química , Tripanossomicidas/química , Trypanosoma/parasitologia , Tripanossomíase Africana/parasitologiaRESUMO
Seven aromatic polyamides and copolyamides were synthesized from two different aromatic diamines: 4,4'-(Hexafluoroisopropylidene)bis(p-phenyleneoxy)dianiline (HFDA) and 2,4-Aminobenzenesulfonic acid (DABS). The synthesis was carried out by polycondensation using isophthaloyl dichloride (1SO). The effect of an increasing molar concentration of the sulfonated groups, from DABS, in the copolymer properties was evaluated. Inherent viscosity tests were carried out to estimate molecular weights. Mechanical tests were carried out under tension, maximum strength ( σ max), Young's modulus (E), and elongation at break (εmax) to determine their mechanical properties. Tests for water sorption and ion exchange capacity (IEC) were carried out. Proton conductivity was measured using electrochemical impedance spectroscopy (EIS). The results indicate that as the degree of sulfonation increase, the greater the proton conductivity. The results obtained showed conductivity values lower than the commercial membrane Nafion 115 of 0.0065 S cm-1. The membrane from copolyamide HFDA/DABS/1S0-70/30 with 30 mol DABS obtained the best IEC, with a value of 0.747 mmol g-1 that resulted in a conductivity of 2.7018 × 10-4 S cm-1, lower than the data reported for the commercial membrane Nafion 115. According to the results obtained, we can suggest that further developments increasing IEC will render membranes based on aromatic polyamides that are suitable for their use in PEM fuel cells.