Synthesis and antimicrobial properties of substituted .beta.-aminoxypropionyl penicillins and cephalosporins

Balsamo, Aldo; Broccali, G; Lapucci, Annalina; Macchia, B.; Macchia, Franco; Orlandini, Elisabetta; Rossello, Armando

doi:10.1021/jm00126a041

Cited by 22 publications

(13 citation statements)

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“…Further, as an extension to these studies, certain β-aminooxypropionyl penicillins and cephalosporin analogues were synthesized and evaluated for their antimicrobial properties . It has been recognized that changes on the side chain linked to the β-lactam nucleus of β-lactam antibiotics exert an influence on acid stability, resistance to enzyme inactivation, potency, and the spectrum of antimicrobial activity.…”

Section: A Cyclic Vs Noncyclic Nonclassical Bioisosteric Replacementsmentioning

confidence: 99%

Bioisosterism: A Rational Approach in Drug Design

1996

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Section: A Cyclic Vs Noncyclic Nonclassical Bioisosteric Replacementsmentioning

confidence: 99%

Bioisosterism: A Rational Approach in Drug Design

1996

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“…The were synthesized as outlined in Scheme 1. Base-catalyzed (KH2-PO4) condensation of O-ethyl-7 (1) or O-propylhydroxy-lamine8 (2) with acrolein afforded mixtures of the corresponding E (3,4) and Z (5,6) unsaturated oxime ethers in a ratio of approximately 7:3, which could not be separated by the usual fractioning techniques. Epoxidation with m-chloroperoxybenzoic acid of the crude mixtures of 3,5 and 4,6 yielded mixtures of the cor-responding E (7,8) and Z (9,10) epoxides in a ratio of about 7:3, which proved to be too unstable to allow separation.…”

Section: Chemistrymentioning

confidence: 99%

The [(Methyloxy)imino]methyl Moiety as a Bioisoster of Aryl. A Novel Class of Completely Aliphatic .beta.-Adrenergic Receptor Antagonists

Macchia¹,

Balsamo²,

Breschi³

et al. 1994

J. Med. Chem.

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Previous studies in the field of beta-adrenergic drugs had supported the hypothesis of the existence of a bioisosterism between the [(methyleneamino)oxy]methyl moiety (C = NOCH2, MAOMM) of type B beta-blocking drugs and the aryl (Ar) of type A beta-blocking agents. In the MAOMM, however, the carbon of the CH2 linked to the oximic oxygen possesses a hybridization (sp3) and a geometry different from those of the corresponding carbon of Ar which possesses an sp2 hybridization. Furthermore, in the MAOMM, in its preferred conformation, the unsaturated portion (C = N) is situated in a spatial area which does not correspond exactly to the area occupied by Ar. The formal inversion of the atomic sequence C = NOCH2 of the MAOMM leads to a different type of group, the [(methyloxy)imino]methyl moiety (CH2ON = C, MOIMM), which, in the E configuration, appears to present greater steric and electronic analogies with an Ar, with respect to the MAOMM. On the basis of these observations, some completely aliphatic (E)-N-(3-amino-2- hydroxypropylidene)(alkyloxy)amino derivatives of type C (11a,b and 12a, b) were synthesized, the their beta-adrenergic properties were compared with those of the corresponding [(methyleneamino)oxy]-methyl isomers of type B (19a, b and 20a, b). The similar beta-adrenergic properties of 11, 12 and 19, 20 evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations, are discussed on the basis of considerations regarding the spatial correspondences and electronic analogies between the MOIMM and the MAOMM.

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“…The combination of an unsaturated element, lone pairs of electrons, and planar geometry of the aldoxime moiety has attracted attention for its potential to mimic a phenyl ring, as illustrated by the (methyloxy)imino]methyl (MOIM) moiety 38b , which is depicted in Figure in its preferred ( E )-conformation. − This topology provides more effective phenyl ring mimicry than the alternative arrangement associated with the (methyleneamino)oxy]methyl (MAOM) moiety 38c by virtue of better topological overlap of the unsaturated elements with a benzene ring.…”

Section: Bioisosteric Replacement Of Terminal Phenyl Ringsmentioning

confidence: 99%

“…An oxime moiety has been shown to have the potential to mimic a meta -substituted phenyl ( I ) or azine ring ( II ) as depicted in Figure A, where the asymmetry of the oxime allows for its deployment in the two complementary topologies, III and IV . , The earliest application of this bioisostere was explored in the context of the nonselective β-adrenergic receptor antagonist dichloroisoproterenol ( 74a ) that was exploited as a useful tool molecule (Figure B). In the examples depicted, the oxime was installed in a fashion that recognized the potential for the two complementary topologies captured in 74b and 74c , with each motif offering further plasticity based on the two potential modes of overlay with 74a depicted in Figure B .…”

Section: Bioisosteric Replacement Of Meta-substituted Phenyl Ringsmentioning

confidence: 99%

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

2021

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The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity in drug design either as a pharmacophore or as a scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at the beginning of the 21st century highlighted the indiscriminate deployment of phenyl rings as an important contributor to the poor physicochemical properties of advanced molecules, which limited their prospects of being developed into effective drugs. This Perspective deliberates on the design and applications of bioisosteric replacements for a phenyl ring that have provided practical solutions to a range of developability problems frequently encountered in lead optimization campaigns. While the effect of phenyl ring replacements on compound properties is contextual in nature, bioisosteric substitution can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG channel.

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Synthesis and antimicrobial properties of substituted .beta.-aminoxypropionyl penicillins and cephalosporins

Cited by 22 publications

References 1 publication

Bioisosterism: A Rational Approach in Drug Design

Bioisosterism: A Rational Approach in Drug Design

The [(Methyloxy)imino]methyl Moiety as a Bioisoster of Aryl. A Novel Class of Completely Aliphatic .beta.-Adrenergic Receptor Antagonists

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

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