Structure-Activity Considerations

Recent review articles and one monograph provide an excellent survey of research on the mechanism of action and the effect of structural modifications on the antibiotic activity of the j8-lactam antibiotics. The penicillins and cephalosporins are believed to exert their antibacterial activity by irreversible acylation of the bacterial transpeptidase responsible for the final cross-linking step in 

Heymes, G. Amiard, and G. Nomine, Bull. Soc. chim. France, 1974, 563. 

A potentially useful route to semi-synthetic penicillins by direct acylation of penicillin G imino-chloride esters (187) proceeds through the intermediate diacyl derivatives (188). Selective removal of the phenylacetyl group and ester deblocking with thiophenolate ion afford penicillins (189). A practical application of this route for the synthesis of carbenicillin [189 R = PhCH(COaH)] has been developed. A route to a-carboxyphenylacetamido-cephalosporins (191), by the reaction of isocyanate (190 R = 4-nitrobenzyl) with the anion of t-butyl phenylacetate, has been described.  

Nomura, T. Fugono, T. Hitaka, I. Minami, T. Azuma, S. Morimoto, and T. Masuda, 

In the absence of greater understanding of the mode of action of the -lactam antibiotics, the generation of structure-activity data has remained one of trial and error. Cycloaddition of acetylenes to the azide of 7-acylamido-3-azidomethylcephalosporanic acids afforded a series of 3-(l,2,3-triazol-l-ylmethyl)cephalosporanic acids while the syntheses of 7-mandeloylaminocephalosporins, 6-thioacylamino-, a-sulpho-, 6-ami-dino-, cyanoamidino-, and levomycetin adipinyl-pencillins have been described in publications. 

Buskooszczi wicz and J. Cieslak, Acta. Polon. Pharm., 1973, 30, 43. 

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The structure-activity considerations at that time naturally enough focussed interest on epoxides formed at the K-regions of the carcinogenic hydrocarbons (Figure 3), but it was not until 1964 that the synthesis of such putative metabolites was achieved (46). 

In general, a well-conducted long-term study in two species, with no indication of immunotoxicity, based on the considerations outlined above, should be adequate to evaluate the potential for drug-induced immunotoxicity. If the results from these studies do not produce evidence of immune-specific toxicity after examination of standard and/or additional hematologic, serum chemical, and histopathologic parameters, then additional testing should not be indicated. However, if there are structure-activity considerations that may indicate a potential for concern, of if... 

Structure-Activity Considerations and Drug-Receptor Interactions... 

Lavenhar, S.R. and Maczka, C.A. (1985). Structure-Activity Considerations in Risk Assessment a Simulation Study. Toxicology Industrial Health, 1,249-259. 

Agonists - The existence of two receptor populations for histamine raises the interesting question of whether the chemical mechanism of histamine interaction differs between the two receptor types. Some indications of the chemical properties which may differentiate receptor action come from studies of histamine chemistry and from structure-activity considerations of congeners. Histamine in aqueous solution is a mixture of equilibrating species, viz. ionic forms, tautomers and conformers nmr studies confirm earlier pK work indicating a N -H N -H (structures 1 and 2) tautomer ratio of approximately 4 1 for histamine monocation, and a comparable ratio for histamine base. The latter result contrasts with crystal structure data and molecular orbital predictions, and may indicate an influence of solvent on tautomer stability. Recent studies of properties pertinent to consideration of ligand-receptor interactions are conformation (MO calculations and infra-red comparison of solid state and chloroform solutions of histamine base ), electronic charge distribution, metal complexation, and phospholipid inter-... 

For a new substance that is to be initially supplied at the base-set level (greater than 1 tonne per annum), information regarding acute and repeated-dose toxicity, skin and eye irritation, skin sensitization and genotoxicity is necessary. Testing to identify any respiratory sensitization hazard is not required, although structure-activity considerations may lead to classification as sensitizing and assignment of R42 (May cause sensitization by inhalation), as described previously for isocyanates. There is also the option to apply the safety phrase S22 ( Do not breathe dust ) in the absence of R42, and this has been done, for example, with certain new, dusty chlorotriazinyl dyestuffs. 

This classification is important to people involved in pharmaceutical research. An expert in peptide or prostaglandin chemistry will be primarily concerned with the various chemical manipulations that can be performed on these molecules and will rely on someone else to screen them for effects against the various illnesses susceptible to peptide or prostaglandin therapy. On the other hand, the chemical classification allows an excellent overview of all the congeners and analogues derived from an initial lead and thus facilitates structure-activity considerations. 

Structure-activity considerations. Predictions of the adverse effects that a substance may have can sometimes be made on the basis of a knowledge of the chemical structure of the substance and an association of various features of that structure with particular types of toxicity. It must be emphasised that this is a field for the expert and uninformed structure-activity predictions can be dangerously misleading. There are some areas, however, in which experts may make such predictions with a fair degree of accuracy. Perhaps the simplest example would be the prediction of irritant or corrosive properties for a molecule likely to give rise to acidic conditions in contact with water. Predictions of mutagenic activity may also in some cases be made by experts on the basis of the potential of the molecule to interact with DNA. 

PHARMACOLOGY Primary prostaglandins Synthetic prostaglandins Structure-activity considerations Endoperoxides PGGj and PGH2 Thromboxanes TXA2 and TXB2 Prostacyclins... 

This class of acids 259 constituted a novel feature and a deviation from the natural model compound chrysanthemic acid. Originating from structure-activity considerations on the similarity of pyrethroid and DDT by Holan [512], they improved the understanding of molecular shape and insecticidal activity. The commercial result of this ideas is cycloprothrin. 

While it complicates matters even further in terms of screening and assessing risk, it is clear from structure-activity considerations that some toxic agents can have multiple modes of action. For instance, the thiouracils not only act as antithyroids but also can serve as a source of electrophilic sulfur during oxidative desulfurization and presumably have antiuracil effects. 

Willhite CC, Wier PJ, Berry D (1989) Dose response and structure activity considerations in retinoic-induced dysmorphogenesis. Crit Rev Toxicol 20 113-135... 

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