Hermenegilda Moreno-Diaz

Antidiabetic activity of N-(6-substituted-1,3-benzothiazol-2-yl)benzenesulfonamides

N-(6-Substituted-1,3-benzothiazol-2-yl)benzenesulfonamide derivatives 1-8 were synthesized and evaluated for their in vivo antidiabetic activity in a non-insulin-dependent diabetes mellitus rat model. Several compounds synthesized showed significant lowering of plasma glucose level in this model. As a possible mode of action, the compounds were in vitro evaluated as 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors. The most active compounds (3 and 4) were docked into the crystal structure of 11beta-HSD1. Docking results indicate potential hydrogen bond interactions with catalytic amino acid residues.

Microwave‐Assisted One‐Pot Synthesis of 2‐(Substituted phenyl)‐1H‐benzimidazole Derivatives

Abstract A series of 2‐(substituted phenyl)‐1H‐benzimidazole derivatives with various 5‐and 6‐position substituents (‐H, ‐CH3, ‐CF3) were synthesized via microwave irradiation using a short synthetic route and Na2S2O5 as oxidant. This simple, fast, and efficient preparation of benzimidazole derivatives has been developed using readily available and inexpensive reagents (aldehydes and 1,2‐phenylenediamines) under solvent‐free conditions.

Synthesis, in vitro and computational studies of protein tyrosine phosphatase 1B inhibition of a small library of 2-arylsulfonylaminobenzothiazoles with antihyperglycemic activity

The 2-arylsulfonylaminobenzothiazole derivatives 1-27 were prepared using a one step reaction. The in vitro inhibitory activity of the compounds against protein tyrosine phosphatase 1B (PTP-1B) was evaluated. Compounds 4 and 16 are rapid reversible (mixed-type) inhibitors of PTP-1B with IC(50) values in the low micromolar range. The most active compounds (4 and 16) were docked into the crystal structure of PTP-1B. Docking results indicate potential hydrogen bond interactions between the nitro group in both compounds and the catalytic amino acid residues Arg 221 and Ser 216. Both compounds were evaluated for their in vivo antihyperglycemic activity in a type 2 diabetes mellitus rat model, showing significant lowering of plasma glucose concentration, during the 7h post-intragastric administration.

Discovery of Thiazolidine-2,4-Dione/Biphenylcarbonitrile Hybrid as Dual PPAR α/γ Modulator with Antidiabetic Effect: In vitro, In Silico and In Vivo Approaches†

A small series of thiazolidine‐2,4‐dione and barbituric acid derivatives 1–4 was prepared using a short synthetic route, and all compounds were characterized by elemental analysis, mass spectrometry, and NMR (1H, 13C) spectroscopy. Their in vitro relative expression of peroxisome proliferator‐activated receptor &agr1; and peroxisome proliferator‐activated receptor &ggr1; was evaluated. Compound 1 showed an increase in the mRNA expression of both peroxisome proliferator‐activated receptor isoforms, as well as the GLUT‐4 levels. The antidiabetic activity of compound 1 was determined at 50 mg/kg single dose using a non‐insulin‐dependent diabetes mellitus rat model. The results indicated a significant decrease in plasma glucose levels. Additionally, we performed a molecular docking of compound 1 into the ligand binding pocket of peroxisome proliferator‐activated receptor &agr1; and peroxisome proliferator‐activated receptor &ggr1;. In these binding models, compound 1 may bind into the active site of both isoforms showing important short contacts with the peroxisome proliferator‐activated receptor &ggr1; residues: Tyr 473, His 449, Ser 289, His 323; and peroxisome proliferator‐activated receptor α residues: Tyr 464, His 440, Ser 280 and Tyr 314.

2-acylamino-5-nitro-1,3-thiazoles: preparation and in vitro bioevaluation against four neglected protozoan parasites.

The 2-acylamino-5-nitro-1,3-thiazole derivatives (1-14) were prepared using a one step reaction. All compounds were tested in vitro against four neglected protozoan parasites (Giardia intestinalis, Trichomonas vaginalis, Leishmania amazonensis and Trypanosoma cruzi). Acetamide (9), valeroylamide (10), benzamide (12), methylcarbamate (13) and ethyloxamate (14) derivatives were the most active compounds against G. intestinalis and T. vaginalis, showing nanomolar inhibition. Compound 13 (IC50=10nM), was 536-times more active than metronidazole, and 121-fold more effective than nitazoxanide against G. intestinalis. Compound 14 was 29-times more active than metronidazole and 6.5-fold more potent than nitazoxanide against T. vaginalis. Ureic derivatives 2, 3 and 5 showed moderate activity against L. amazonensis. None of them were active against T. cruzi. Ligand efficiency indexes analysis revealed higher intrinsic quality of the most active 2-acylamino derivatives than nitazoxanide and metronidazole. In silico toxicity profile was also computed for the most active compounds. A very low in vitro mammalian cytotoxicity was obtained for 13 and 14, showing selectivity indexes (SI) of 246,300 and 141,500, respectively. Nitazoxanide showed an excellent leishmanicidal and trypanocidal effect, repurposing this drug as potential new antikinetoplastid parasite compound.

Synthesis of 2-{2-[(α/β-naphthalen-1-ylsulfonyl)amino]-1,3-thiazol-4-yl} acetamides with 11β-hydroxysteroid dehydrogenase inhibition and in combo antidiabetic activities ☆

Compounds 1-10 were designed using a bioisosteric approach and were prepared using a short synthetic route. The in vitro inhibitory activity of the compounds against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was evaluated. Compounds 5 (α-series) and 10 (β-series) had a moderate inhibitory enzyme activity (55.26% and 67.03% inhibition at 10 μM, respectively) and were as active as BVT.14225 (positive control). Both compounds have a piperidine ring in their structure, but the most active (10) was selected to establish its in vivo antidiabetic effect using a non insulin-dependent diabetes mellitus rat model. The antidiabetic activity of compound 10 was determined at 50 mg/kg single dose in an acute model, and also by short term sub-chronic administration for 5 days. The results indicated a significant decrease of plasma glucose levels, similar than BVT.14225. Additionally, a molecular docking of the most active compounds of each series into the ligand binding pocket of one subunit of human 11β-HSD1 was performed. In this model the oxygen atom of the sulfonamide make hydrogen bond interactions with the catalytic residues Ser170 and Ala172. We also observed important π-π interactions between the naphthyl group and Tyr177.

2-(4-Methoxyphenyl)-1H-benzimidazole

In the title compound, C14H12N2O, the dihedral angle between the benzimidazole ring system and the 4-methoxyxadphenyl substituent is 34.12u2005(6)°. The molxadecules are linked by interxadmolecular N—H⋯N hydrogen bonds, forming chains running along the c axis.

2-(2-Benzyl­oxyphen­yl)-1H-benzimid­azole

The asymmetric unit of the title compound, C20H16N2O, contains two molecules. The dihedral angles between the benzimidazole ring systems and the attached benzene rings are 10.6u2005(5) and 13.7u2005(5)°. The conformers are linked by bifurcated three-centre hydrogen bonds, forming chains along the diagonal of the a b plane. The packing is further stabilized by π–π and C—H⋯π interactions.

2-(2-Methoxyphenyl)-1H-benzimidazole

The asymmetric unit of the title compound, C14H12N2O, contains two different conformational isomers of 2-(2-methoxyxadphenxadyl)-1H-benzimidazole. The dihedral angles between the benzimidazole ring systems and the 2-methoxyxadphenyl substituents are 26.9u2005(3) and −13.3u2005(3)°. The conformers are linked by bifurcated three-centre hydrogen bonds, forming chains running along the a axis. The packing is further stabilized by offset and edge-to-face π–π interxadactions.

4-Meth­oxy-N-[6-methyl-2,3-dihydro-1,3-benzothia­zol-2-yl­idene]benzene­sulfonamide

The title compound, C15H14N2O3S2, is of interest with respect to its biological activity. The crystal structure is stabilized by intermolecular N—H⋯N, C—H⋯O and C—H⋯π hydrogen-bonding interactions, as well as offset π–π interactions [distance between the centroids of the aryl and thiazole rings of adjacent molecules of 3.954u2005(2)u2005Å].