Structure-activity, relations

The antibacterial activity of the ansamycins varies to a large extent. In most cases, antibacterial activity parallels the inhibition of the bacterial RNA polymerase and 

This would be consistent with the finding that chemical substitutions at C-3 and C-4 of the molecule in many cases have little effect on its interaction with the enzyme68, 71. Effects on eukaryotic and viral enzymes observed after the introduction of substituents in these positions are most probably not due to specific binding such as is found with the bacterial enzyme. 

Although many facts are known about the structure-activity relations of ansamy-cins, some problems remain unsolved. Rifamycin W, for instance, (Fig. 6) does not 

Another puzzle is posed by naphthomycin. The fact that it does not inhibit RNA polymerase can be explained by the absence of a hydroxyl group at C-8. However, it shows antibacterial activity against gram-positive strains that is counteracted by SH-containing substances such as cystein28. Naphthomycin is therefore an example of an ansamycin with antibacterial activity not due to inhibition of RNA polymerase. 

The structure of the ansamycins determines not only their activity on RNA polymerase, but also other important characteristics such as their ability to penetrate into bacteria and their pharmacokinetics and absorption in the host. To cite just a few examples rifamycin B, containing a free carboxylic acid group, has no antibacterial activity, although it inhibits RNA polymerase as strongly as rifampicin. Damavaricin C behaves similarly to rifamycin B, whereas its 6-methyl ether inhibits RNA polymerase to a lesser extent, but has good antibacterial activity23. Rifampicin owes its widespread clinical use to the fact that, in contrast to most other rifamycin derivatives, it is well absorbed when given orally. 

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Keywords Arabinogalactans Bioactivity Medicinal plants Rhamnogalacturonans Pectins Structure-activity relations... 

This review will focus on pectic substances that have been shown to exhibit biological activity. Their structure, bioactivity and possible structure activity relations will be discussed. 

Zmuidinavicius D, Didziapetris R, Japertas P, Avdeef A and Petrauskas A. Classification structure-activity relations (C-SAR) in prediction of human intestinal absorption. J Pharm Sci 2003 92 621-33. 

SEERAM N P and NAIR M G (2002) Inhibition of lipid peroxidation and structure-activity-related studies of the dietary constituents autocyanins, autocyanidins, and catechins, JAgric Food Chem, 50, 5308-12. 

Musings on ADME predictions and structure-activity relations. Chem. Biodivers. 2005, 2,1411-1427. 

Skinner, W. A. Structure-activity relations in the vitamin E series. I. Effects of 5-methyl substitution on 6-hydroxy-2,2,5,7 8-pentamethylchroman.7. Med. Chem. 1967,10,657-661. 

The structure-activity relation of triterpene QMs on the anti-inflammatory effect has been investigated with a series of analogues by comparing inhibition of the IL-1 (3 production in the LPS-induced monocytes.93-94 Clearly, the conjugated QM structure with alkenes is essential for the observed inhibition, and similar inhibitory effect was found with derivatives that are capable to form the conjugated QM through hydrolysis and/or oxidation.93-94 Also, the presence of the E ring in the triterpene QM structure is an additional contributor. 

Szabo S, Reynolds ES, Unger SH. 1982. Structure-activity relations between alkyl nucleophilic chemicals causing duodenal ulcer and adrenocortical necrosis. J Pharmacol Exp Ther 223 68-76. 

Cooper, G.H., I.W. Lawston, R.L. Rickard, and T.D. Inch. "Structure-Activity Relations in 2,6,7-Trio xa-l-phosphabicyclo[2.2.2]octanes and Related Compounds." European Journal of Medicinal Chemistry 13 (1978) 207-212. 

Development of quantitative structure activity relations for use in evaluating toxicity of organotin compounds (Hall and Pinkney 1985 Laughlin and Linden 1985 Laughlin et al. 1985 Laughlin 1987). 

Vasko, M. R., Lutz, M. P., and Domino, E. F. (1974) Structure activity relations of some indolealkylamines in comparison to phenethylamines on motor activity and acquisition of avoidance behavior. Psychopharmacologia, 36 49-58. 

Gaffield, W. and Keeler, R.F. (1994). Structure-activity relations of teratogenic natural products, Pure and Appl. Chem., 66, 2407-2410. 

QSAR = quantitative structure activity relations, cf e.g. Jastorff, Stormann, Wolcke 2003... 

Trieff NM, Ramanujam VMS, Stara IF, et al. 1991. Water quality criteria assessment for chlorinated benzenes using the quantitative structure activity relation approach and porphyrogenic endpoint in rats. Int J Environ Health Res 1 215-230. 

Amidines. After the initial observation that formamidines are agonists for OA receptors in the firefly (14,15 58), these compounds have been shown to mimic OA in virtually every insect system known to contain OA receptors, including the DUMETi system (59)f the glandular lobe of the corpus cardiacum (60) and the fat body ( ) of the locust, and various CNS adenylate cyclase preparations (26-28). The structure-activity relations of amidines as octopaminergic agonists have been examined in several systems including adenylate cyclase stimulation in the firefly lantern and... 

Hudson, B. D., George, A. R., Ford, M. G., and Livingstone, D. J. (1992) Structure-activity relation ships of pyrethroid insecticides. Part 2. The use of molecular dynamics for conformation searching and average parameter calculation.. /. Comput-Aided Mol. Design 6, 191-201. 

Given atomic coordinates for a particular conformation of a molecule and some property value assigned to each atom, one can easily calculate a chirality function that distinguishes enantiomers, is zero for an achiral molecule, and is a continuous function of the coordinates and properties. This is useful as a quantitative measure of chirality for molecular modeling and structure-activity relations. 

T. Granier, N. Panday, and A. Vasella, Structure-activity relations of imidazo-pyridine-type inhibitors of P-D-glucosidases, Helv. Chim. Acta, 80 (1997) 979-987. 

Other families of compounds that also possess the same function. If we have a hint on how these diverse structures give rise to the sensation of musk, we would be in a much better position to find the other families of compounds. In the case of perfume and smell, the objective should perhaps be termed structure-activity relations (SARs), instead of the more lofty title of QSAR. 

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