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Exploring Synthetic Dihydrobenzofuran and Benzofuran Neolignans as Antiprotozoal Agents against Trypanosoma cruzi.

ABSTRACT: Chagas disease is a neglected tropical disease that affects more than 8 million people. Although there are therapies against this disease, the search for new drugs is important because the current treatments show limited effectiveness and high toxicity. In this work, eighteen dihydrobenzofuran-type neolignans (DBNs) and two benzofuran-type neolignans (BNs) were synthesized and evaluated against amastigote forms of two Trypanosoma cruzi strains. The in vitro cytotoxicity and hemolytic activity of the most active compounds were also evaluated and their relationships with T. cruzi tubulin DBNs were investigated by an in silico approach. Four DBNs demonstrated activity against the T. cruzi Tulahuen lac-Z strain (IC₅₀ from 7.96 to 21.12 µM), and DBN 1 exhibited the highest activity against the amastigote forms of the T. cruzi Y strain (IC₅₀ 3.26 μM). Compounds 1-4 showed CC₅₀ values higher than antitrypanosomal activities, except for DBN 3. All DBNs with antitrypanosomal activity demonstrated CH₅₀ higher than 100 µM. The in silico results indicated that DBNs 1, 2, and 4 are capable of destabilizing the dynamics of the tubulin-microtubule from the vinca site. These compounds displayed promising in vitro activity against T. cruzi, especially compound 1, and can be considered molecular prototypes for the development of new antiparasitic drugs.

SUBMITTER: Pagotti MC

PROVIDER: S-EPMC10052957 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Exploring Synthetic Dihydrobenzofuran and Benzofuran Neolignans as Antiprotozoal Agents against <i>Trypanosoma cruzi</i>.

Pagotti Mariana C MC Dias Herbert J HJ Candido Ana Carolina B B ACBB Oliveira Thaís A S TAS Borges Alexandre A Oliveira Nicoli D ND Lopes Carla D CD Orenha Renato P RP Parreira Renato L T RLT Crotti Antônio E M AEM Magalhães Lizandra G LG

Pharmaceutics 20230224 3

Chagas disease is a neglected tropical disease that affects more than 8 million people. Although there are therapies against this disease, the search for new drugs is important because the current treatments show limited effectiveness and high toxicity. In this work, eighteen dihydrobenzofuran-type neolignans (DBNs) and two benzofuran-type neolignans (BNs) were synthesized and evaluated against amastigote forms of two <i>Trypanosoma cruzi</i> strains. The in vitro cytotoxicity and hemolytic acti ...[more]

PMID: 36986617

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Project description:Benzofuran and 2,3-dihydrobenzofuran scaffolds are heterocycles of high value in medicinal chemistry and drug synthesis. Targeting inflammation in cancer associated with chronic inflammation is a promising therapy. In the present study, we investigated the anti-inflammatory effects of fluorinated benzofuran and dihydrobenzofuran derivatives in macrophages and in the air pouch model of inflammation, as well as their anticancer effects in the human colorectal adenocarcinoma cell line HCT116. Six of the nine compounds suppressed lipopolysaccharide-stimulated inflammation by inhibiting the expression of cyclooxygenase-2 and nitric oxide synthase 2 and decreased the secretion of the tested inflammatory mediators. Their IC50 values ranged from 1.2 to 9.04 µM for interleukin-6; from 1.5 to 19.3 µM for Chemokine (C-C) Ligand 2; from 2.4 to 5.2 µM for nitric oxide; and from 1.1 to 20.5 µM for prostaglandin E2. Three novel synthesized benzofuran compounds significantly inhibited cyclooxygenase activity. Most of these compounds showed anti-inflammatory effects in the zymosan-induced air pouch model. Because inflammation may lead to tumorigenesis, we tested the effects of these compounds on the proliferation and apoptosis of HCT116. Two compounds with difluorine, bromine, and ester or carboxylic acid groups inhibited the proliferation by approximately 70%. Inhibition of the expression of the antiapoptotic protein Bcl-2 and concentration-dependent cleavage of PARP-1, as well as DNA fragmentation by approximately 80%, were described. Analysis of the structure-activity relationship suggested that the biological effects of benzofuran derivatives are enhanced in the presence of fluorine, bromine, hydroxyl, and/or carboxyl groups. In conclusion, the designed fluorinated benzofuran and dihydrobenzofuran derivatives are efficient anti-inflammatory agents, with a promising anticancer effect and a combinatory treatment in inflammation and tumorigenesis in cancer microenvironments.

Dataset Information

Exploring Synthetic Dihydrobenzofuran and Benzofuran Neolignans as Antiprotozoal Agents against Trypanosoma cruzi.

Publications

Exploring Synthetic Dihydrobenzofuran and Benzofuran Neolignans as Antiprotozoal Agents against <i>Trypanosoma cruzi</i>.

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