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14 pages, 5577 KiB

Open AccessArticle

Antibacterial Activity of Squaric Amide Derivative SA2 against Methicillin-Resistant Staphylococcus aureus

by Moxi Yu, Yachen Hou, Meiling Cheng, Yongshen Liu, Caise Ling, Dongshen Zhai, Hui Zhao, Yaoyao Li, Yamiao Chen, Xiaoyan Xue, Xue Ma, Min Jia, Bin Wang, Pingan Wang and Mingkai Li

Antibiotics 2022, 11(11), 1497; https://doi.org/10.3390/antibiotics11111497 - 28 Oct 2022

Cited by 4 | Viewed by 2636

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA)-caused infection is difficult to treat because of its resistance to commonly used antibiotic, and poses a significant threat to public health. To develop new anti-bacterial agents to combat MRSA-induced infections, we synthesized novel squaric amide derivatives and evaluated their anti-bacterial activity by determining the minimum inhibitory concentration (MIC). Additionally, inhibitory activity of squaric amide 2 (SA2) was measured using the growth curve assay, time-kill assay, and an MRSA-induced skin infection animal model. A scanning electron microscope and transmission electron microscope were utilized to observe the effect of SA2 on the morphologies of MRSA. Transcriptome analysis and real-time PCR were used to test the possible anti-bacterial mechanism of SA2. The results showed that SA2 exerted bactericidal activity against a number of MRSA strains with an MIC at 4–8 µg/mL. It also inhibited the bacterial growth curve of MRSA strains in a dose-dependent manner, and reduced the colony formation unit in 4× MIC within 4–8 h. The infective lesion size and the bacterial number in the MRSA-induced infection tissue of mice were reduced significantly within 7 days after SA2 treatment. Moreover, SA2 disrupted the bacterial membrane and alanine dehydrogenase-dependent NAD⁺/NADH homeostasis. Our data indicates that SA2 is a possible lead compound for the development of new anti-bacterial agents against MRSA infection. Full article

(This article belongs to the Special Issue New Natural Products as Candidates for the Discovery of Anti-MRSA Drugs)

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19 pages, 3462 KiB

Open AccessArticle

Chiral Aminoalcohols and Squaric Acid Amides as Ligands for Asymmetric Borane Reduction of Ketones: Insight to In Situ Formed Catalytic System by DOSY and Multinuclear NMR Experiments

by Yana Nikolova, Georgi M. Dobrikov, Zhanina Petkova and Pavletta Shestakova

Molecules 2021, 26(22), 6865; https://doi.org/10.3390/molecules26226865 - 14 Nov 2021

Cited by 6 | Viewed by 3308

Abstract

A series of squaric acid amides (synthesized in 66–99% isolated yields) and a set of chiral aminoalcohols were comparatively studied as ligands in a model reaction of reduction of α-chloroacetophenone with BH₃•SMe₂. In all cases, the aminoalcohols demonstrated better efficiency (up to 94% ee), while only poor asymmetric induction was achieved with the corresponding squaramides. A mechanistic insight on the in situ formation and stability at room temperature of intermediates generated from ligands and borane as possible precursors of the oxazaborolidine-based catalytic system has been obtained by ¹H DOSY and multinuclear 1D and 2D (¹H, ^10/11B, ¹³C, ¹⁵N) NMR spectroscopy of equimolar mixtures of borane and selected ligands. These results contribute to better understanding the complexity of the processes occurring in the reaction mixture prior to the possible oxazaborolidine formation, which play a crucial role on the degree of enantioselectivity achieved in the borane reduction of α-chloroacetophenone. Full article

(This article belongs to the Special Issue Asymmetric Synthesis of Pharmaceutically Relevant and Natural Compounds)

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19 pages, 1286 KiB

Open AccessArticle

Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors

by Barbora Svobodova, Eva Mezeiova, Vendula Hepnarova, Martina Hrabinova, Lubica Muckova, Tereza Kobrlova, Daniel Jun, Ondrej Soukup, María Luisa Jimeno, José Marco-Contelles and Jan Korabecny

Biomolecules 2019, 9(8), 379; https://doi.org/10.3390/biom9080379 - 19 Aug 2019

Cited by 32 | Viewed by 6012

Abstract

Tacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we combined this scaffold with different tacrine-based derivatives. In this study, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various AChEIs. All new derivatives were evaluated for their anti-cholinesterase activities, cytotoxicity using HepG2 cell line and screened to predict their ability to cross the blood-brain barrier. In this contribution, we also report in silico studies of the most potent AChE and BChE inhibitors in the active site of these enzymes. Full article

(This article belongs to the Special Issue Advances in Cholinesterases)

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