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

Abstract

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.

Bioisosterism: A Rational Approach in Drug Design

“…Further, in its preferred conformation, the unsaturated portion (CN) of the MAOMM, is situated spatially in an area which does not exactly correspond to the area occupied by the aryl group. An attempt to optimize these differences resulted in the formal inversion of the atomic sequence CNOCH 2 of the MAOMM ( 20 , Figure ) which lead to a different bioisostere, the [(methyloxy)imino]methyl moiety (CH 2 ONC, MOIMM) ( 21 , Figure ) . This moiety, in the E configuration, presents greater steric and electronic analogies to an aryl group as compared to MAOMM by virtue of similarities in hybridization and geometry.…”

“…An attempt to optimize these differences resulted in the formal inversion of the atomic sequence CdNOCH 2 of the MAOMM (20, Figure 49) which lead to a different bioisostere, the [(methyloxy)imino]methyl moiety (CH 2 ONdC, MOIMM) (21, Figure 49). 83 This moiety, in the E configuration, presents greater steric and electronic analogies to an aryl group as compared to MAOMM by virtue of similarities in hybridization and geometry. This similarity explains the retention of β 1 -adrenergic binding affinity and activity (Table 34) on replacement of the MAOMM (22, Figure 50) with MOIMM (23, Figure 50).…”

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

“…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 .…”

Synthesis, Antifungal Activity, and Molecular Modeling Studies of New Inverted Oxime Ethers of Oxiconazole

“…Moreover, for these last compounds, the results obtained for the chemical shift values of the groups linked directly to their iminic carbon are consistent with those reported in the literature for similar oxime ether derivatives with the E configuration. 9 On the contrary, for compounds of type 8, the spectroscopic data presently available do not allow us to indicate the exact configuration around their iminic double bond.…”

“…So, type 7 derivatives may represent a further development of studies of the groups linked to the C(2) of the ethane chain of the pharmacophore of these antifungal agents. Finally, the same type of inversion of the atomic sequence of the CN−O group had led to positive results in other classes of drugs, such as β-adrenergic antagonists, β-lactam antibiotics, and neuroleptics, and the development of these studies, also through theoretical research, had made it possible to hypothesize the existence of a bioisosteric relationship of the methyleneaminoxy group, CN−O, with the methyloxyimino group, O−NC …”