Synthesis and antibacterial activity of C-4 substituted monobactams.

Antimicrobial resistance represents a global threat to healthcare. The ability to adequately treat infectious diseases is increasingly under siege due to the emergence of drug-resistant microorganisms. New approaches to drug development are especially needed to target organisms that exhibit broad antibiotic resistance due to expression of β-lactamases which is the most common mechanism by which bacteria become resistant to β-lactam antibiotics. We designed and synthesized 20 novel monocyclic β-lactams with alkyl- and aryl-thio moieties at C4, and subsequently tested these for antibacterial activity. These compounds demonstrated intrinsic activity against serine β-lactamase producing Mycobacterium tuberculosis wild type strain (Mtb) and multiple (n = 6) β-lactamase producing Moraxella catarrhalis clinical isolates.

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“…β-Lactams 22 and 24 (Scheme 7), 26–28 (Scheme 8) were synthesized from 4-acetoxy-2-azetidone 1 , using procedures described previously. 10,27 …”

Section: Resultsmentioning

confidence: 99%

C4-Alkylthiols with activity against Moraxella catarrhalis and Mycobacterium tuberculosis

Kostova

Myers

Beck

et al. 2011

Bioorganic & Medicinal Chemistry

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“…4, Table I). 92 The most active member in this series, oxysulfonamide 16a, displayed an interesting spectrum of activity against E. cloacae, E. coli, Klebsiella pneumoniae, P. vulgaris, and S. marcescens (MICs of 0.03-4 μg/mL). Growth of P. aeruginosa was mainly inhibited by compound 16b (MIC of 8 μg/mL) ( Fig.…”

Section: B 3-[2-(2-aminothiazol-4-yl)-2-(oxyimino) Acetamido]monobacmentioning

confidence: 93%

Antibacterial and β‐Lactamase Inhibitory Activity of Monocyclic β‐Lactams

Decuyper

Jukič

Sosič

et al. 2017

Medicinal Research Reviews

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Due to the widespread emergence of resistant bacterial strains, an urgent need for the development of new antibacterial agents with novel modes of action has emerged. The discovery of naturally occurring monocyclic β-lactams in the late 1970s, mainly active against aerobic Gram-negative bacteria, has introduced a new approach in the design and development of novel antibacterial β-lactam agents. The main goal was the derivatization of the azetidin-2-one core in order to improve their antibacterial potency, broaden their spectrum of activity, and enhance their β-lactamase stability. In that respect, our review covers the updates in the field of monocyclic β-lactam antibiotics during the last three decades, taking into account an extensive collection of references. An overview of the relationships between the structural features of these monocyclic β-lactams, classified according to their N-substituent, and the associated antibacterial or β-lactamase inhibitory activities is provided. The different paragraphs disclose a number of well-established classes of compounds, such as monobactams, monosulfactams, monocarbams, monophosphams, nocardicins, as well as other known representative classes. Moreover, this review draws attention to some less common but, nevertheless, possibly important types of monocyclic β-lactams and concludes by highlighting the recent developments on siderophore-conjugated classes of monocyclic β-lactams.

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“…Aryl-carbaldehyde oxime derivatives 7-(4-Hydroxyphenyl)-1-benzofuran-4-carbaldehyde oxime US200611591039 [220] Benzisoxazoles 3-(5-Hydroxy-2-naphthyl)-1,2-benzisoxazol-6-ol US2005S11093792 [221] Benzoxazoles 2-(2,3-Difluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol US200210309699 US200611636947 [222,223] Cylcohexyl derivatives 4-(4-Hydroxy-phenyl)-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-methyl-cylcohex-3-enecarboxylic acid ethyl ester US200711624808 [224] (Diaryl-methyl)-malononitriles 2-[(2-Methoxyphenyl)(1-naphthyl)methyl]malononitrile US200511124808 [225] Hydroxy-biphenyl-carbaldehyde oxime derivatvies 3-Chloro-4'hydroxy-2'-methyl-1,1'-biphenyl-4-carbaldehyde US200410835228 [226] ER , ER Tetrahydroisoquinolines 1-(4 -Pyrroidinoethoxyphenyl)-2-(4 -fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline US200310615282 US200511071955 [227,228] 3 Adiol derivatives 5,7-Dihydroxy-3-(4-hydroxyphenyl)chromen-4-one US200310690169 [229] Dibenzo chromene derivatives 3-(Acetyloxy)-7-bromo-5H-dibenzo[c,g]chromen-9-y] acetate US200611591042 [230] Hydrochloride salts Cylcoalkyl-4-triisopropylsilyloxy-acetophenones US200310385808 [231] (Hydroxyphenyl)-1H-indole-3-carbaldehyde oxime derivatives 1-(4-Benzyloxyphenyl)-2-methyl-1H-indole-3-carbaldehyde US200711765548 [232] Pyrrolo …”

Section: Acknowledgementsmentioning

confidence: 99%

Modulators of Vascular Sex Hormone Receptors and their Effects in Estrogen-Deficiency States Associated with Menopause

Serock¹,

Wells²,

Khalil³

2008

PRC

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Cardiovascular disease (CVD) is more prevalent in postmenopausal than premenopausal women, suggesting vascular protective effects of estrogen. Also, experimental studies have demonstrated beneficial effects of estrogen in improving vascular function and reducing vascular injury. However, clinical trials including HERS I, HERS II, WHI and WISDOM have demonstrated minimal beneficial vascular effects of menopausal hormone therapy (MHT) in postmenopausal women with CVD. The discrepancies between the experimental findings and clinical data may be related to the vascular estrogen receptors (ER), the type, route of administration, or dosage of MHT, and subject's age. Vascular ERs mediate both genomic and non-genomic effects of estrogen on the endothelium, vascular smooth muscle (VSM), and extracellular matrix (ECM). Postmenopausal changes in vascular ER structure, polymorphisms, amount, subcellular location, affinity or signaling could modify their responsiveness to estrogen and thereby the outcome of MHT. Recent investigations and patents have been centered on developing new ER modulators and alternatives for the traditional natural and synthetic forms of MHT which carry the risk of invasive breast cancer and venous thromoboembolism. Phytoestrogens may have similar effects as traditional MHT and have not demonstrated harmful side effects. Specific estrogen receptor modulators (SERMs) such as raloxifene and tamoxifen have also been tested. ER agonists that selectively target ERalpha, ERbeta and perhaps GPR30 may modify specific vascular signaling pathways. Also, the dose, route of administration, and timing of MHT are integral to optimizing the beneficial effects and minimizing the side effects of MHT. Progesterone, testosterone and modulators of their specific receptors may also affect the overall vascular effects of MHT in estrogen-deficiency states associated with menopause.

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Synthesis and antibacterial activity of C-4 substituted monobactams.

Cited by 10 publications

References 4 publications

C4-Alkylthiols with activity against Moraxella catarrhalis and Mycobacterium tuberculosis

C4-Alkylthiols with activity against Moraxella catarrhalis and Mycobacterium tuberculosis

Antibacterial and β‐Lactamase Inhibitory Activity of Monocyclic β‐Lactams

Modulators of Vascular Sex Hormone Receptors and their Effects in Estrogen-Deficiency States Associated with Menopause

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