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In this study, we synthesized a series of seven benzimidazole derivatives incorporating the structural acidic framework of angiotensin II (Ang II) type 1 receptor (AT 1 R) antagonists (ARA-II) employing a three-step reaction sequence. The chemical structures were confirmed by 1 H NMR, 13 C NMR and mass spectral data. Through biosimulation, compounds 1-7 were identified as computational safe hits, thus, best candidates underwent ex vivo testing against two distinct mechanisms implicated in hypertension: antagonism of the Ang II type 1 receptor and the blockade of calcium channel. Molecular docking studies helped to understand at the molecular level the dual vasorelaxant effects with the recognition sites of the AT 1 R and the L-type calcium channel. In an in vivo spontaneously hypertensive rat model (SHR), intraperitoneally administration of compound 1 at 20 mg/kg resulted in a 25 % reduction in systolic blood pressure, demonstrating both ex vivo vasorelaxant action and in vivo antihypertensive multitarget efficacy. ©2024 Elsevier., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In current work, we prepared a series of nine 4-benzyloxy-5-benzylidene-1,3-thiazolidine-2,4-diones using a two-step pathway. Compounds 1-9 were tested in vitro using a set of three proteins recognized as important targets in diabetes and related diseases: PPARα, PPARγ, and GLUT-4. Compounds 1-3, 5, and 7 showed significant increases in the mRNA expression of PPARγ and GLUT-4, whereas compounds 1-3 did it over PPARα. Compounds 1-3 were identified as a dual PPAR α/γ modulators and were selected for evaluating the in vivo antidiabetic action at 100 mg/kg dose, being orally actives and decreasing blood glucose concentration in a hyperglycemic mice model, as well as reducing the triacylglycerides levels in normolipidemic rats. Docking and molecular dynamics studies were conducted to clarify the dual effect and binding mode of compounds 1-3 on both PPARs. Compounds 2 and 3 exhibited robust in vitro and in vivo efficacy and could be considered dual PPAR modulators with antidiabetic and antidyslipidemic effects., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We designed and synthesized five new 5-nitrothiazole-NSAID chimeras as analogues of nitazoxanide, using a DCC-activated amidation. Compounds 1-5 were tested in vitro against a panel of five protozoa: 2 amitochondriates (Giardia intestinalis, Trichomonas vaginalis) and 3 kinetoplastids (Leishmania mexicana, Leishmania amazonensis and Trypanosoma cruzi). All chimeras showed broad spectrum and potent antiprotozoal activities, with IC 50 values ranging from the low micromolar to nanomolar order. Compounds 1-5 were even more active than metronidazole and nitazoxanide, two marketed first-line drugs against giardiasis. In particular, compound 4 (an indomethacin hybrid) was one of the most potent of the series, inhibiting G. intestinalis growth in vitro with an IC 50 of 0.145μM. Compound 4 was 38-times more potent than metronidazole and 8-times more active than nitazoxanide. The in vivo giardicidal effect of 4 was evaluated in a CD-1 mouse model obtaining a median effective dose of 1.709μg/kg (3.53nmol/kg), a 321-fold and 1015-fold increase in effectiveness after intragastric administration over metronidazole and nitazoxanide, respectively. Compounds 1 and 3 (hybrids of ibuprofen and clofibric acid), showed potent giardicidal activities in the in vitro as well as in the in vivo assays after oral administration. Therefore, compounds 1-5 constitute promising drug candidates for further testing in experimental chemotherapy against giardiasis, trichomoniasis, leishmaniasis and even trypanosomiasis infections., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Six derivatives (1-6) of moronic acid were semi-synthesized and their in vitro protein tyrosine phosphatase 1B (PTP-1B) inhibition activity assessed. Derivatives 2 (IC50=10.8 ± 0.5 μM) and 6 (IC50=7.5 ± 0.1 μM) displayed the most potent inhibitory activity. Therefore, they (50mg/Kg) were tested for their antidiabetic effect in vivo using a non-insulin dependent diabetes mellitus rat model. The results indicated that they decrease plasma glucose levels during all the experiment (p <0.05). Docking analysis of 2 and 6 with PTP-1B orthosteric site A and allosteric site B, showed that 2 had polar and Van der Waals interactions in both sites with Val49, Gln262, Met258, Phe182, Ala217, Ile219 and Gly259, displaying more affinity for site A. Compound 6 showed polar interaction with Gln262 and Van der Waals with Val49, Ile219, Gly259, Arg254, Ala27, Phe52, Met258, Asp48 and Phe182, suggesting that the potential binding site is localized in site B, close to the catalytic site A. Therefore, derivatives 2 and 6 have potential for the development of antidiabetic agents., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Compound {4-[({4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}acetyl)amino]phenoxy}acetic acid (1) was prepared and the in vitro relative expression of PPARγ, GLUT-4 and PPARα, was estimated. Compound 1 showed an increase of 2-fold in the mRNA expression of PPARγ isoform, 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 (NIDDM) rat model. The in vivo results indicated a significant decrease of plasma glucose levels, during the 7 h post-administration. Also, we performed a molecular docking of compound 1 into the ligand binding pocket of PPARγ, showing important short contacts with residues Ser289, His323 and His449 in the active site., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Stansin 6 a tetrasaccharide resin glycoside isolated from the root of Ipomoea stans was evaluated as anticonvulsant and neuroprotective in kainic acid-induced seizures of rats. Intraperitoneal injection of kainic acid (10 mg/kg) induced typical behavioral seizures such as wet dog shakes and limbic seizures, and histopathological changes in the hippocampus (degeneration and loss of pyramidal cells in CA1 to CA4 areas). Stansin 6 (10-80 mg/kg) had no effect on the behavior of rats and did not induce hippocampal damage. Pretreatment with stansin 6 inhibited convulsions in rats from kainic acid-induced seizures, reduced the degeneration pattern in the CA3 region, decreased astrocytic reactivity, and reduced the expression of IL-1β and TNF-α induced by kainic acid. These results suggest that stansin 6 possesses neuroprotective and anticonvulsant activities., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A tetrazole isosteric analogue of clofibric acid (1) was prepared using a short synthetic route and was characterized by elemental analysis, NMR ((1)H, (13)C) spectroscopy, and single-crystal X-ray diffraction. The in vitro inhibitory activity of 1 against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was evaluated, showing a moderate inhibitory enzyme activity (51.17% of inhibition at 10 μM), being more active than clofibrate and clofibric acid. 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 of plasma glucose levels, during the 7h post-administration. Additionally, we performed a molecular docking of 1 into the ligand binding pocket of one subunit of human 11β-HSD1. In this model, compound 1 binds into the catalytic site of 11β-HSD1 in two different orientations. Both of them, show important short contacts with the catalytic residues Ser 170, Tyr 183, Asp 259 and also with the nicotinamide ring of NADP(+)., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

We have synthesized two new benzologues of Nitazoxanide (NIT) and Tizoxanide (TIZ), using a short synthetic route. Both compounds were tested in vitro against six protozoa (Giardia intestinalis, Trichomonas vaginalis, Entamoeba histolytica, Plasmodium berghei, Leishmania mexicana and Trypanosoma cruzi). Compound 1 (benzologue of NIT) showed broad antiprotozoal effect against all parasites tested, showing IC(50)'s<5 μM. This compound was five-times more active than NIT, and 18-times more potent than metronidazole against G. intestinalis. It was 10-times more active than pentamidine against L. mexicana, and it was sevenfold more potent than benznidazole versus T. cruzi. This compound could be considered as a new broad spectrum antiprotozoal agent., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Tyrianthins A (1) and B (2), two new partially acylated glycolipid ester-type heterodimers were isolated from Ipomoea tyrianthina. Scammonic acid A was determined as the glycosidic acid in both monomeric units. Tyrianthin A (1) (IC(50) 0.24+/-0.09 microM and E(max) 81.80+/-0.98%), and tyrianthin B (2) (IC(50) 0.14+/-0.08 microM and E(max) 87.68+/-0.72%) showed significant in vitro relaxant effect on aortic rat rings, in endothelium- and concentration-dependent manners. Also, these compounds were able to increase the release of GABA and glutamic acid in brain cortex, and displayed weak antimycobacterial activity.

A series of ten novel hybrids from benzimidazole and pentamidine were prepared using a short synthetic route. Each compound was tested in vitro against the protozoa Trichomonas vaginalis, Giardia lamblia, Entamoeba histolytica, Leishmania mexicana, and Plasmodium berghei, in comparison with pentamidine and metronidazole. Some analogues showed high bioactivity in the low micromolar range (IC(50)<1 microM) against the first four protozoa, which make them significantly more potent than either standard. 1,5-bis[4-(5-methoxy-1H-benzimidazole-2-yl)phenoxy]pentane (2) was 3- and 9-fold more potent againstG. lamblia than metronidazole and pentamidine, respectively. This compound was 23-, 108-, and 13-fold more active than pentamidine against T. vaginalis, E. histolytica and L. mexicana, respectively. Studying further structure-activity relationships through the use of bioisosteric substitution in these hybrids should provide new leads against protozoal diseases.

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.

A simple, fast, and efficient method for the preparation of several 2-(alkyloxyaryl)-1H-benzimidazole derivatives is reported. Compounds were synthesized through a rapid one-pot three component reaction via microwave irradiation, starting from commercially available aldehydes and o-phenylenediamine, in the presence of Na(2)S(2)O(5) and solvent-free conditions. The design of these compounds explore the hypothesis that the stilbene framework could be mimicked with an appropriate 2-(Alkyloxyphenyl)benzimidazole scaffold. This framework has a similar structural motif as the 6-phenylnaphthalene and behaves like stilbene bioisosteres. The spasmolytic activity of these compounds was recorded using isolated rat ileum test. Compound 12 was the most active of the series, showing an IC(50) of 1.19 microM.

Compounds 1-18 have been synthesized and tested in vitro against the protozoa Giardia lamblia, Entamoeba histolytica and the helminth Trichinella spiralis. Inhibition of rat brain tubulin polymerization was also measured and compared for each compound. Results indicate that most of the compounds tested were more active as antiprotozoal agents than Metronidazole and Albendazole. None of the compounds was as active as Albendazole against T. spiralis. Although only compounds 3, 9 and 15 (2-methoxycarbonylamino derivatives) inhibited tubulin polymerization, these were not the most potent antiparasitic compounds.

2-(Trifluoromethyl)benzimidazole derivatives substituted at the 1-, 5-, and 6-positions have been synthesized and in vitro tested against the protozoa Giardia lamblia, Entamnoeha histolytica. and the helminth Trichinella spiralis. Results indicate that all the compounds tested are more active as antiprotozoal agents than Albendazole and Metronidazole. One compound (20) was as active as Albendazole against T. spiralis. These compounds were also tested for their effect on tubulin polymerization and none inhibited tubulin polymerization.