Isosteric molecules

Benzacridine tetrahydroepoxides and did epoxides. The isosteric molecules BA, benz[a]acridine (BaAcr) and benz[c]acridine (BcAcr) and their derivatives provide excellent probes for studying the effect of electronic changes upon biological properties. The... 

Isosteres Molecules or ions of similar size and the same number of valence electrons... 

The main criterion for isosterism is that two isosteric molecules must present similar, if not identical, volumes, and shapes. Ideally, isosteric compounds should be isomorphic and able to cocrystallize. Among the other physical properties that isosteric compounds usually share one can cite boiling point, density, viscosity, and thermal conductivity. However, certain properties must be different dipolar moments, polarity, polarization, size, and shape (e.g. in comparing E and OH , the size and the shape of H cannot be totally neglected). After all, the external orbital may be hybridized differently. 

The assumption of resemblance reveals a second, subtler, presupposition. The periodic chart places elements in columns, or groups, based on the numbers of their valence electrons. Thus, nitrogen is placed in group 5 (15 in the IUPAC scheme) even though it frequently expresses a valence of three. Fixed-period molecules with the same total number of atomic valence-shell electrons ( isoelectronic, horizontally isoelectronic, or isosteric molecules such as N2 and CO) usually have properties more similar than do molecules selected at random. Molecules whose atoms come from different periods but have the same numbers of valence electrons ( vertically isoelectronic or isovalenf molecules such as the salts LiF, Nal, and CsCl), often have somewhat similar properties. So, the sum of the atomic valence electron counts, i.e., the sum of the atomic group numbers, is important. Thus, it appears that using... 

Table 26. Heats of formation of isosteric molecules (kcal/mol)...

As expected for isosteric molecules diphenyldiazomethane (220) (117) exhibits a uv spectrum which is very similar to that of diphenylketene (46), in particular, if the tt.tt bands are taken into consideration. 

Mulliken s interest in the electronic levels in molecules in the 1920s was stimulated by suggestions that their molecular spectra bore similarities to atomic spectra and definite relationships could be discerned for isosteric molecules. He found that the spectroscopic analogy between isosteric molecules could be extended to atoms with the same number of electrons, and this relatirmship was to lead subsequently to the united atom approach. He and Birge classified the electronic states in diatomic molecules using the same Russell-Saunders classification used previously for atomic states. Himd s theoretical analysis [ 149,162-166] of the nature of electronic states in molecules therefore proved to be timely for Mulliken and led him to publish [167-171] a summary of the theory and provide extra experimental evidence supporting it. In the molecular orbital theory Hund showed how the concept of atomic orbitals and the mathematical procedures developed to define them could... 

If the fraction of sites occupied is 0, and the fraction of bare sites is 0q (so that 00 + 1 = 0 then the rate of condensation on unit area of surface is OikOo where p is the pressure and k is a constant given by the kinetic theory of gases (k = jL/(MRT) ) a, is the condensation coefficient, i.e. the fraction of incident molecules which actually condense on a surface. The evaporation of an adsorbed molecule from the surface is essentially an activated process in which the energy of activation may be equated to the isosteric heat of adsorption 4,. The rate of evaporation from unit area of surface is therefore equal to... 

It will be noted that Na is isosteric with the tetradeprotonated urea molecule, (H2N)2C=-0, and is also isoelectronic and isostructural with and N03. An X-ray analy-... 

The isosteric relationship of benzene and thiophene has often led medicinal chemists to substitute the sulfur containing heterocycle for benzene drugs in biologically active molecules. That this relationship has some foundation in fact is attested by the observation that the resulting analogs often possess full biologic activity. Alkylation of the diamine, 71 (obtained from aniline and the chloroethylamine), with 2-chloromethylthiophene affords the antihistamine methaphenylene (72) The correspond-... 

The concept of isosterism 481 has been used in medicinal chemistry. Molecules or groups which possess physicochemical similarity (e.g., similarity in size or the number of valence electrons) are called isosteres. The classical isosteres include, for instance, the following two pairs of groups ... 

More recently, screening efforts at Novartis have identified a hydroxamic acid containing a benzothiazinone ring system (32) [108]. This inhibitor is very potent versus S. aureus Ni -PDF (<5nM) and displays good selectivity versus matrix metalloprotease-2 (MMP-2) and MMP-13. Unfortunately (32), and all other analogues prepared, such as carbon isosteres (33), sulfones (34), N-substituted analogues (35) and N-formyl-N-hydroxylamines (36), lacked appreciable antibacterial activity in spite of their potent enzyme inhibitory activity. Further studies performed by Novartis suggest that these molecules are unable to penetrate the outer cell membrane of E. coli, and may bind to the cell membrane of S. aureus [108]. 

The applicability of such VS in combination with tools available include situations where portions of any molecule need replacement with bioisosteric fragments. In this regard, BROOD software [105] and MOE [222] provide automated tools for fragment removal, replacement, and minimization to relieve any strain in the molecular assembly step and provide a database of fragments(isosteres) that could be enhanced in custom fashion by an enterprise as well. These software allow facile FBVS in 3D. Since this software has become available within the last 2 years, there seem to be a dearth of use cases in the published literature. However, anecdotal reports indicate that these are being used regularly in industry and the Websites of these two vendors provide adequate information for the inquisitive reader. 

This approach has been mainly applied to peptide-based inhibitors of proteases, where the inhibitory molecule is a peptide with a transition state isostere appended to it, and the cognate substrate is simply a peptide of the same amino acid sequence, but lacking the isostere functionality. Examples where good correlations between the free energy of inhibitor binding and the free energy of kcJKM have been found, include peptide-trifluoromethyl ketone inhibitors of human leukocyte elastase (Stein et al., 1987) and peptide-phosphonamidate inhibitors of the metalloprotease ther-molysin (Bartlett and Marlowe, 1983). 

Also the bio-isosteric potential of the pyridazine system hitherto remained largely unexplored, despite the fact that several examples discussed in this review indicate that the replacement of aromatic moieties in bio-ac-tive compounds by the highly polar pyridazine nucleus may well improve the pharmacodynamic and/or the pharmacokinetic profile of a drug molecule. 

A third dataset was built in order to demonstrate that the descriptor is relevant for estimating binding affinity in a QSAR analysis. This last dataset contains 49 HIV-1 protease inhibitors, the 3D coordinates of which were those used by Pastor et al. (30). It has the four transition-state isosteres—hydroxy ethylene, hydroxyethylamine, statine, and a symmetrical diol. The X-ray structures of molecules numbered 1 and 3-34 have been reported (31), whereas molecules numbered 35-50 were modeled on the crystallographic structure of the complex of HIV-1 protease with L-689,502 solved at 2.25 A resolution (32). The binding affinity is expressed as pIC50 values. 

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