Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors

Dražić, Tonko; Sachdev, Vinay; Leopold, Christina; Patankar, Jay V.; Malnar, Martina; Hečimović, Silva; Levak-Frank, Sanja; Habuš, Ivan; Kratky, Dagmar

doi:10.1016/j.bmc.2015.03.067

Cited by 16 publications

(7 citation statements)

References 24 publications

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“…Flash column chromatography was performed with silica gel 60 as the stationary phase. 1 H Nuclear magnetic resonance (NMR) spectra (400 MHz) and 13 polarimeter. Benzyl (2S)-2-(tert-butoxycarbonylamino)-4-oxobutanoate 5 [28] was prepared as previously described [29].…”

Section: Chemistrymentioning

confidence: 99%

“…Since the discovery of benzylpenicillin in 1928, β-lactams emerged as one of the most important and well-studied class of compounds in both the organic and the medicinal chemistry fields [1][2][3][4][5][6][7][8][9][10]. Although the huge impact of β-lactams on public health has been mainly associated with its antibiotic activity, several molecules containing the β-lactam core showed potential activity against other diseases, namely as cholesterol absorption inhibitors, β-lactamase inhibitors, antitumoral and antiviral agents [6,[11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“….29-7.36 (m, 10H). NMR13 C (CDCl3, 100 MHz) δ = 25.4, 26.1, 31.7, 33.2, 43.1, 59.5, 63.7, 68.0, 78.8, 95.1, 101.1, 126.8, 127.7, 128.2, 128.5, 128.6, 128.7, 138.9, 139.0, 166.8, 168.0, 168.4, 172.4. HRMS (ESI-TOF) m/z: [M+H] + Calcd for C27H26N4O5S [M+H] + 519.1691; found 519.1697.…”

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confidence: 99%

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Spiro-Lactams as Novel Antimicrobial Agents

Alves

Caratão

et al. 2020

CTMC

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Introduction: Structural modulation of previously identified lead spiro-β-lactams with antimicrobial activity was carried out. Objective: The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity. Methods: The target chiral spiro-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-γ-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium of a wide range of spiro-β-lactams and spiro-γ-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM) were identified. Results: A novel synthetic route to chiral spiro-γ-lactams has been established. The studied β- and γ- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs. Conclusion: The designed structural modulation of biologically active spiro-β-lactams involved the replacement of the four-membered β-lactam ring by a five-membered γ-lactam ring. Although conformational and superimposition computational studies revealed no significant differences between β- and γ- lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a similar biological profile. The observed results suggest that the β-lactamic core is a requirement for the activity against both HIV and Plasmodium.

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Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Spiro-Lactams as Novel Antimicrobial Agents

Alves

Caratão

et al. 2020

CTMC

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“…[1] Coronary atherosclerosis, a lipid-driven inflammatory disease, is the principal cause of CAD. [3] [4] Over the past 30 years, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have been known to lower the risk of cardiovascular events and overall mortality proportional to suppressing cholesterol biosynthesis and thus have become the predominant lipid-lowering drugs for patients with hyperlipidemia. The total blood cholesterol level is primarily regulated by two complementary mechanisms: de-novo biosynthesis in the liver and the absorption of dietary cholesterol in the small intestine.…”

Section: Introductionmentioning

confidence: 99%

“…The total blood cholesterol level is primarily regulated by two complementary mechanisms: de-novo biosynthesis in the liver and the absorption of dietary cholesterol in the small intestine. [3] [4] Over the past 30 years, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have been known to lower the risk of cardiovascular events and overall mortality proportional to suppressing cholesterol biosynthesis and thus have become the predominant lipid-lowering drugs for patients with hyperlipidemia. [5] [6] Nonetheless, severe side effects that result from high-dose statin treatment, such as hepatotoxicity and myopathy, remain a limiting factor for clinical therapy.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of 2‐Azetidinone and 1H‐Pyrrole‐2,5‐dione Derivatives as Cholesterol Absorption Inhibitors for Reducing Inflammation Response and Oxidative Stress

Xia

Zhu

Yuan

et al. 2019

Chemistry & Biodiversity

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Excess lipid accumulation can initiate the development and progression of atherosclerotic lesions, thus eventually leading to cardiovascular disease. Lipid-lowering medication therapy is one of the cornerstones of cardiovascular disease therapy. On the basis of the cholesterol absorption inhibitor ezetimibe, we successfully synthesized seven 2-azetidinone derivatives and eighteen 1H-pyrrole-2,5-dione derivatives. Most of the new compounds significantly inhibited cholesterol uptake in vitro. In addition, one of the most active inhibitors, compound 14q, showed no cytotoxicity in L02 and HEK293T cell lines. Further evaluation indicated 14q considerably inhibited the amount of TNF-α, ROS, MDA, and LDH in vitro. Therefore, 14q might be a novel cholesterol absorption inhibitor.

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Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.

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Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors

Abstract: Graphical abstract

Cited by 16 publications

References 24 publications

Spiro-Lactams as Novel Antimicrobial Agents

Spiro-Lactams as Novel Antimicrobial Agents

Synthesis and Evaluation of 2‐Azetidinone and 1H‐Pyrrole‐2,5‐dione Derivatives as Cholesterol Absorption Inhibitors for Reducing Inflammation Response and Oxidative Stress

Medicinal Chemistry of β‐Lactam Antibiotics

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