RESUMO
This work aimed to evaluate the inhibition of Candida rugosa lipase by five guanylhydrazone derivatives through biological, biophysical and theoretical studies simulating physiologic conditions. The compound LQM11 (IC50â¯=â¯14.70⯵M) presented the highest inhibition against the enzyme. Therefore, for a better understanding of the interaction process, spectroscopic and theoretical studies were performed. Fluorescence and UV-vis assays indicate a static quenching mechanism with non-fluorescent supramolecular complex formation and changing the native protein structure. The binding process was spontaneous (ΔGâ¯<â¯0) and electrostatic forces (ΔHâ¯<â¯0 and ΔSâ¯>â¯0) played a preferential role in stabilizing the complex ligand-lipase. The compounds were classified as non-competitive inhibitors using orlistat as a reference in competition studies. Based on the 1H NMR assays it was possible to propose the sites of ligand (epitope) that bind preferentially to the enzyme and the theoretical studies were consistent with the experimental results. Finally, LQM11 was efficient as a lipase inhibitor of the crude intestinal extract of larvae of Rhynchophorus palmarum, an important agricultural plague, showing potential for control of this pest. Within this context, the real potential of this biotechnological application deserves further studies.
Assuntos
Candida/enzimologia , Inibidores Enzimáticos/farmacologia , Hidrazonas/farmacologia , Lipase/antagonistas & inibidores , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Animais , Biotecnologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Hidrazonas/química , Hidrazonas/isolamento & purificação , Lipase/metabolismo , Estrutura Molecular , Termodinâmica , Gorgulhos/químicaRESUMO
In this work, a combined matrix isolation FTIR and theoretical DFT(B3LYP)/6-311++G(d,p) study of 2-furaldehyde dimethylhydrazone (2FDH) was performed. According to calculations, two E and two Z conformers exist, the E forms having considerably lower energy than the Z forms. The absence of relevant sterical hindrance between the two substituents around the CN bond (dimethylamino and 2-furyl) in the E structures and an extended π-p electron delocalization in the hydrazone moiety determines the higher stability of these species relatively to the Z structures. In the lowest energy form (E-AG) the O-C-CN and CN-N-Lp (Lp=lone electron pair of amine nitrogen atom) dihedral angles are predicted by the calculations to be -177.2° and 93.7°, respectively. The weak (NC)-Hâ¯O hydrogen bond type interaction (Hâ¯O distance: 252.2 pm) in form E-AG, together with the absence in this form of the destabilizing interaction between the lone electron pairs of the oxygen and nitrogen atoms existing in E-SG, explains its lower energy in comparison with this latter form. Both E-AG and E-SG conformers could be trapped from room temperature gas phase in low temperature argon and xenon matrices. The high E-SGâE-AG energy barrier (>25 kJ mol(-1)) explains that, upon increasing the temperature of the matrices no conformational isomerization could be observed. After irradiation of 2FDH with UV-light at λ>328 and λ>234 nm, two different photochemistries were observed. Irradiation at lower energy (λ>328nm) induced the E-AGâE-SG isomerization. Further irradiation at higher energy (λ>234 nm) led to a quick consumption of 2FDH and production of furan and dimethylisocyanide.
Assuntos
Argônio/química , Furaldeído/análogos & derivados , Hidrazonas/química , Hidrazonas/isolamento & purificação , Processos Fotoquímicos/efeitos da radiação , Raios Ultravioleta , Xenônio/química , Furaldeído/química , Furaldeído/isolamento & purificação , Conformação Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , TermodinâmicaRESUMO
Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis, which remains a serious public health problem. The emergence of resistant bacterial strains has continuously increased and new treatment options are currently in need. In this work, we identified a new potential aldehyde-arylhydrazone-oxoquinoline derivative (4e) with interesting chemical structural features that may be important for designing new anti-TB agents. This 1-ethyl-N'-[(1E)-(5-nitro-2-furyl)methylene]-4-oxo-1,4-dihydroquinoline-3-carbohydrazide (4e) presented an in vitro active profile against M. tuberculosis H37Rv strain (minimum inhibitory concentration, MIC = 6.25 µg/mL) better than other acylhydrazones described in the literature (MIC = 12.5 µg/mL) and close to other antitubercular agents currently on the market. The theoretical analysis showed the importance of several structural features that together with the 5-nitro-2-furyl group generated this active compound (4e). This new compound and the analysis of its molecular properties may be useful for designing new and more efficient antibacterial drugs.