Studies on the interaction between HSA and new halogenated metformin derivatives: influence of lipophilic groups in the binding ability.

In the type II diabetes mellitus, Metformin hydrochloride is recommended as a common FAD approved drug. Synthesis of novel metformin series has been widely explored, mainly due to its biological importance and to improve their pharmacokinetic profile. Generally, human serum albumin (HSA) is the main protein used to study drug viability in vitro analysis. Thus, the present study reports the synthesis of three new halogenated metformin derivatives (MFCl, MFBr and MFCF3) and its interaction toward HSA by multiple spectroscopic techniques (UV-Vis, circular dichroism, steady-state, time-resolved and synchronous fluorescence), combined to computational methods (molecular docking and quantum chemical calculation). The interaction between each halogenated metformin derivative and HSA is spontaneous (ΔG°<0), entropically driven (ΔS°>0), moderate (Ka and Kb ≈ 104 M-1) and occurs preferentially in the subdomain IIA (close to Trp-214 residue). Molecular docking results suggested hydrogen bonding, van der Waals and hydrophobic interactions as the main binding forces. Quantum chemical calculations suggested imino groups as the most intense electrostatic negative potentials, while the positive electrostatic potential is located at the hydrogen atoms on N,N-dimethyl and the phenyl systems which can help the hydrophobic interactions. [Formula: see text]Communicated by Ramaswamy H. Sarma.

Monoamine oxidase inhibitory activity of methoxy-substituted chalcones.

The MAO-B inhibitory activity of chalcone (1, 3- diphenyl-2-propen-1-one) based compounds arise from its structural similarity with 1, 4-diphenyl-2-butene, a known MAO-B inhibitor. Based on our previous report, the methoxy-substituted with fluorine containing chalcones are promising reversible MAO-B inhibitors, while in the present study, a series of methoxylated chalcones (C1-C9) bearing substitution on the para position of ring B was synthesized and evaluated for their human monoamine oxidase inhibitory activity. With the exception of (2E)-1-(4-methoxyphenyl)-3-(4-nitrophenyl) prop-2-en-1-one (C7), which is a nonselective inhibitor, the chalcones exhibited competitive, selective, and reversible inhibition of hMAO-B. The most potent compound, (2E)-3-[4-(dimethylamino) phenyl]-1-(4-methoxyphenyl) prop-2-en-1-one (C5), showed the best inhibitory activity towards hMAO-B (IC50=0.29±0.011µM;Ki=0.14±0.001µM). The reversibility of MAO-B inhibition by compound C5 was demonstrated by the recovery of enzyme activity after dialysis of mixtures containing enzyme and inhibitor. The reversiblity of C5 was 25.38±1.40 and 92.00±3.87% before and after dialysis, respectively. PAMPA was carried out to evaluate the blood-brain barrier effects of the designated compounds. Moreover, the most potent MAO-B inhibitor, C5, was found to be nontoxic towards cultured hepatic cells at 5 and 25µM, with 97 and 90% viability. Molecular docking study was performed against hMAO-B to observe the binding site interactions of the lead compound.