Drugs and Drug Candidates

13 pages, 1254 KiB

Open AccessArticle

Synthesis, Characterization, and Activity of Hydroxymethylnitrofurazone Nanocrystals against Trypanosoma cruzi and Leishmania spp.

by Cauê Benito Scarim, Aline de Souza, Débora Soares Souza Marins, Elda Gonçalves dos Santos, Lívia de Figueiredo Diniz Castro, Ivo Santana Caldas, Patrícia Ferreira Espuri, Marcos José Marques, Elizabeth Igne Ferreira, Nadia Araci Bou-Chacra and Chung Man Chin

Drugs Drug Candidates 2022, 1(1), 43-55; https://doi.org/10.3390/ddc1010005 - 13 Dec 2022

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Abstract

Hydroxymethylnitrofurazone (NFOH) is a prodrug of nitrofurazone devoid of mutagenic toxicity, with in vitro and in vivo activity against Trypanosoma cruzi (T. cruzi) and in vitro activity against Leishmania. In this study, we aimed to increase the solubility of NFOH to improve its efficacy against T. cruzi (Chagas disease) and Leishmania species (Leishmaniasis) highly. Two formulations of NFOH nanocrystals (NFOH-F1 and NFOH-F2) were prepared and characterized by determining their particle sizes, size distribution, morphologies, crystal properties, and anti-trypanosomatid activities. Furthermore, cytotoxicity assays were performed. The results showed that the optimized particle size of 108.2 ± 0.8 nm (NFOH-F1) and 132.4 ± 2.3 nm (NFOH-F2) increased the saturation solubility and dissolution rate of the nanocrystals. These formulations exhibited moderate anti-Leishmania effects (Leishmania amazonensis) in vitro and potent in vitro activity against T. cruzi parasites (Y strain). Moreover, both formulations could reduce parasitemia (around 89–95% during the parasitemic peak) in a short animal model trial (Y strain from T. cruzi). These results suggested that the increased water solubility of the NFOH nanocrystals improved their activity against Chagas disease in both in vitro and in vivo assays. Full article

(This article belongs to the Collection Anti-Parasite Drug Discovery)

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14 pages, 2242 KiB

Open AccessArticle

Xanthene Derivatives Targeting Bacterial Efflux Pumps, Quorum-Sensing, and Biofilm Formation

by Miguel Maia, Fernando Durães, Diana I. S. P. Resende, Nikoletta Szemerédi, Luís Gales, Paulo Martins-da-Costa, Madalena Pinto, Gabriella Spengler and Emília Sousa

Drugs Drug Candidates 2022, 1(1), 29-42; https://doi.org/10.3390/ddc1010004 - 06 Dec 2022

Cited by 3 | Viewed by 1673

Abstract

The rise of multidrug resistance (MDR) bacteria in nosocomial and health-care institutions is widespread and is currently recognized as a major medical challenge. Mechanisms of bacterial resistance, namely, quorum sensing (QS), biofilm formation, and efflux pumps, have been identified as critical biological processes in MDR bacteria. Following previous reports on the activity of phenothiazines against mechanisms of bacterial resistance, in this work we focus on the synthesis of xanthene derivatives aiming to discover phenothiazine bioisosteres with improved activity. Four compounds were obtained from the conjugation of xanthydrol with sulfonamides and aniline and were fully characterized. Their antibacterial activity was assessed considering their minimum inhibitory concentration (MIC) against Gram-positive and Gram-negative strains, efflux pump inhibition, influence on biofilm formation and quorum-sensing (QS) inhibition. It was observed that the MIC of all the tested compounds was above 64 µg/mL The four 9-xanthenyl derivatives obtained, particularly the xanthene sulfonamide derivatives 3b and 3c, showed promising results on QS inhibition with a reduction of pigment production of 48 and 41 mm, and on biofilm formation with a reduction of 78 and 79%, respectively. Full article

(This article belongs to the Section Medicinal Chemistry and Preliminary Screening)

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7 pages, 460 KiB

Open AccessFeature PaperOpinion

Failed Repurposing of Lysosomotropic Drugs for COVID-19 Treatment or Prevention

by François Marceau

Drugs Drug Candidates 2022, 1(1), 22-28; https://doi.org/10.3390/ddc1010003 - 02 Dec 2022

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Abstract

The hope for the rapid discovery of an effective drug therapy for COVID-19 has led to several efforts to repurpose drugs approved for other indications. Lysosomotropic drugs, organic amines such as chloroquine, hydroxychloroquine, amiodarone and many others, were found to interfere with the viral life cycle in vitro but have failed in clinical trials. The properties of lysosomotropic drugs and the vacuolar cytopathology induced by them are briefly reviewed, including the critical role of lipophilicity, the central role of vacuolar (V)-ATPase for their concentration in acidic organelles, the altered function of these organelles including impaired endocytosis and secretion, macroautophagic accumulation and secondary phospholipidosis. The apparent preferential uptake of lysosomotropic drugs by phagocytic leukocytes (macrophages, neutrophils) and the high concentrations needed for a sustained disruption of vacuolar trafficking may have contributed to the failure of lysosomotropic drug repurposing for COVID-19. Full article

(This article belongs to the Special Issue Fighting SARS-CoV-2 and Related Viruses)

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19 pages, 7459 KiB

Open AccessArticle

Synthesis, Selective Cytotoxic Activity against Human Breast Cancer MCF7 Cell Line and Molecular Docking of Some Chalcone-Dihydropyrimidone Hybrids

by Eduardo B. Mass, Carolina A. de Lima, Marcelo G. M. D’Oca, Juliana M. Sciani, Giovanna B. Longato and Dennis Russowsky

Drugs Drug Candidates 2022, 1(1), 3-21; https://doi.org/10.3390/ddc1010002 - 01 Dec 2022

Cited by 2 | Viewed by 1894

Abstract

Designed Chalcone-Dihydropyrimidinone hybrid compounds were synthesized expeditiously. The hybridization was performed through the Copper-catalyzed Alkyne-Azide Cycloaddition (CuAAC) from the propargyloxy chalcones and azido-dihydropyrimidinones. The hybrid products were prepared in five steps with a 30–48% overall yield. Most of the compounds showed selective cytotoxicity and lower IC₅₀ values (<10 µM) against MCF-7 (breast adenocarcinoma) cancer. Cytotoxicity was also observed against OVCAR-3 (ovary, adenocarcinoma), NCI/ADR-RES (ovary, multidrug-resistant adenocarcinoma), and U-251 (brain, glioblastoma) cell lines. The potency of the most active hybrids 9d, 9g, and 9h was greater than the individual parental compounds, suggesting the effectiveness of molecular hybridization on the cytotoxicity. Compounds 9d, 9g, and especially 9h showed high selectivity for breast cancer cells (MCF-7) regarding human keratinocytes (HaCaT). Molecular docking calculations for the 9d, 9g, and 9h hybrids in the active site of estrogen supported the hypothesis that the compounds act as ER-α antagonists, disrupting the cell proliferation process of MCF-7, corroborating the potency and selectivity observed for this tumoral cell line. Full article

(This article belongs to the Section Medicinal Chemistry and Preliminary Screening)

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