Structure-activity relationships isosterism

Table 3 Structure-Activity Relationships Reported for Structural Analogues and Isosteres of 2,3,7,8-TetrachIorodibenzo-p-dioxin (TCDD) ... 

The workers at American Cyanamid present some of the synthetic and biological characteristics of the sulfur analogs of their imidazoline family of herbicides. This is an example of replacing the carbonyl of the imidazoli-none with an isosteric moiety. This is an interesting account of the synthesis and structure-activity relationships in a very active series of herbicides. 

Halogens (particularly chlorine) can be replaced by other electron-attracting functions snch as trifluoromethyl or cyano groups. In the antibiotic chloramphenicol, both the chlorine atoms of the dichloroacetic moiety and of the para-nitro-phenyl group yielded productive isosteric replacements (Table 15.6). Many other examples of univalent atoms or groups replacements are found in the chapter dealing with substituent effects (Chapter 20) and with quantitative structure-activity relationships (Chapter 23). 

Indomethacin and Analogs - Among several isosteric modifications of indomethacin studied at Merck, an indene isoster, cis -1-p-chloro-benzylidenyl-5-methoxy-2-methyl-3-indenylacetic acid (VII), was found to be half as active as indomethacin. The corresponding "trans isomer was only one-tenth as active. The structure-activity relationship of Nj-aroyl and N.-aralkyl indole acetic acids is generally parallel to that of indene isosters, indicative of a similar mode of action. Based on X-ray diffraction data, the nonplanar configuraticn of the cis-isomer was suggested as the preferred conformation of... 

In conclusion, our data demonstrate that the incorporation of 7-azatryptophan into proteins can be of broad applicability in structure-activity relationship studies, where a Trp-isostere is required, or as a spectroscopic probe in the study of protein folding and binding [90],... 

The design of enzyme inhibitors has included random screening of synthetic chemical agents, natural products, and combinatorial libraries followed by molecular optimization or structure-activity relationships of so-called lead structures as well as bio-isosteric analogues of the enzyme substrates themselves. Drugs (e.g., finasteride) also have been developed for one indication but, based on observed side effects, have lead to other uses. 

Several important features of a-MSH structure-activity relationships were revealed by these studies (Table 2). First, replacement of methionine-4 by the pseudo-isosteric amino acid norleucine is completely compatible with hormone-... 

R 645 S. Oishi, Structure-Activity Relationship Studies on Cyclic RGD Peptides Utilizing Novel Alkene Dipeptide Isosteres , Yakugaku Zas-shi, 2004,124,269... 

The data shown in Table 2 illustrate the general paucity of comparative toxicity data within an isosteric series of chemicals. In this Table a variety of toxic end-points observed for benzene and naphthalene have been compared with those of their simple heterocyclic analogues, and it is clear that it is almost impossible to derive chemical structure-biological activity relationships from the published literature for even such a simple series of compounds. Even basic estimates of mammalian toxicity such as LD50 values cannot be accurately compared due either to the absence of relevant data or the noncomparability of those available. Thus in a field where there are little comparative data on the relative toxicity to mammals of pyrrole, thiophene and furan for example, it is difficult to relate chemical structure to biological activity in historical heterocyclic poisons such as strychnine (3) and hemlock [active agent coniine (4)]. 

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