Structure-activity relationship groups

The fundamental assumption of SAR and QSAR (Structure-Activity Relationships and Quantitative Structure-Activity Relationships) is that the activity of a compound is related to its structural and/or physicochemical properties. In a classic article Corwin Hansch formulated Eq. (15) as a linear frcc-cncrgy related model for the biological activity (e.g.. toxicity) of a group of congeneric chemicals [37, in which the inverse of C, the concentration effect of the toxicant, is related to a hy-drophobidty term, FI, an electronic term, a (the Hammett substituent constant). Stcric terms can be added to this equation (typically Taft s steric parameter, E,). 

Completely ah initio predictions can be more accurate than any experimental result currently available. This is only true of properties that depend on the behavior of isolated molecules. Colligative properties, which are due to the interaction between molecules, can be computed more reliably with methods based on thermodynamics, statistical mechanics, structure-activity relationships, or completely empirical group additivity methods. 

As can be seen from Table 3, only modifications at the 6/3-amino groups have been successful in producing penicillins of medical significance up to this time. Several reviews have dealt with the structure-activity relationship in this area in considerable detail B-80MI51102, B-77MI51106, B-75MI51102) and should be consulted for the actual effects of structural modification on antibacterial activity. 

Exploratory research on structure activity relationships in the meperidine series revealed the interesting fact that the oxygen atom and carbonyl group of this molecule could often be interchanged. That is, the so-called "reversed meperidine" (C) still exhibits analgesic activity in experimental animals. (Note that, except for the interchange, the rest of the molecule is unchanged.)... 

The structure activity relationships ( SAR) of newly synthesized analogues of nucleosides, xanthine heterocycles, and nonxanthine heterocycles have been explored at the ARs. Potent and selective AR antagonists have been prepared for all four subtypes [3, 4], and selective agonists are known for three subtypes [1]. Thus, numerous pharmacological tools are available for in vitro and in vivo use (Table 2). Potent and selective A2b AR agonists are yet to be repotted, although several research groups have identified lead compounds. 

More entries were used to test the valT3ity of equation 6 for reaction 1 than for the other families of initiators (Table I). Six of the thirteen entries for reaction 1 have AE(x) values bunched between -21 and -24 kcal/mole. It was felt that, by using all of these six entries, any bias in structure activity relationships would be decreased for this region of radical pi-delocalization energies. This group also includes those diazenes which are most used commercially, such as 2,2 -azobisisobutyronitrile (AIBN - entry 16 ) and dimethyl 2,2 -azobisisobutyrate (entry 14). 

Most relevant for the affinity for A9-THC and analogs to CB-receptors are the phenolic hydroxyl group at C-1, the kind of substitution at C-9, and the properties of the side chain at C-3. Relating to the structure-activity relationships (SAR) between cannabinoids and the CB-receptors, many different modified strucfures of fhis subsfance group were developed and fesfed. The most important variations include variations of the side chain at the olivetolic moiety of the molecules and different substitutions at positions C-11 and C-9. One of the most popular analogous compounds of A9-THC is HU-210 or (-)-trans-ll-OH-A8-THC-DMH, a cannabinoid with a F,l-dimethylheptyl side... 

In 1985, it was reported by Hsiang et al. [43] that the cytotoxic activity of 20-(S)-camptothecin (CPT III) was attributed to a novel mechanism of action involving the nuclear enzyme topo I, and this discovery of unique mechanism of action revived the interest in CPT and its analogues as anticancer agents. CPT stabilizes the covalent, reversible topo I-DNA complex leading to the inhibition of DNA synthesis in mammalian cells and interferes with the topo I breakage-reunion reaction [44]. Clinical trials and structure-activity relationships have demonstrated the requirement of the a-hydroxy group, the... 

Suzuki et al. [52] synthesized a series of isoaurostatin derivatives (VIII) and evaluated their inhibitory activities as well as structure-activity relationships against topo I and II. They predicted from their results that the addition of hydroxyl groups on aromatic rings increases the activity. From the in-... 

Abstract Protoberberine alkaloids and related compounds represent an important class of molecules and have attracted recent attention for their various pharmacological activities. This chapter deals with the physicochemical properties of several isoquinoline alkaloids (berberine, palmatine and coralyne) and many of their derivatives under various environmental conditions. The interaction of these compounds with polymorphic DNA structures (B-form, Z-form, H -form, protonated form, triple helical form and quadruplex form) and polymorphic RNA structures (A-form, protonated form, triple helical form and quadruplex form) reported by several research groups, employing various analytical techniques such as spectrophotometry, spectrofluorimetry, circular dichro-ism, NMR spectroscopy, viscometry as well as molecular modelling and thermodynamic analysis to elucidate their mode and mechanism of action for structure-activity relationships, are also presented. 

Lipophilicity is the measure of the partitioning of a compound between a lipidic and an aqueous phase [1]. The terms lipophilicity and hydrophobicity are often used inconsistently in the literature. Lipophilicity encodes most of the intramolecular forces that can take place between a solute and a solvent. Hydrophobicity is a consequence of attractive forces between nonpolar groups and thereby is a component of lipophilicity [2]. Lipophilicity is one of the most informative physicochemical properties in medicinal chemistry and since long successfully used in quantitative structure-activity relationship (QSAR) studies. Its... 

The first non-peptide oxytocin antagonists, based on a spiropiperidine template, were described by Merck in 1992 [68-70]. The binding affinity data for key compounds from this series are summarised in Table 7.2. The initial screening hit, L-342,643, (23), had modest (4/iM) affinity for rat uterine oxytocin receptors and very little vasopressin selectivity [71]. A structure activity relationship (SAR) study was carried out around this template, focussing on the toluenesulphonamide group. This work led to the identification of bulky lipophilic substitution as key to improved oxytocin potency, while the introduction of a carboxylic acid group led to improved... 

Perhaps the advantage of the medicinal chemistry route lies in the flexibility of introducing different alkyl groups on the primary amine through reductive amination on 2-aminoethyl indole 10 and hence allows access to various N, N-dialkyl tryptamine derivatives for structure-activity relationship (SAR) studies. 

Johannsen and colleagues (1977) report dermal LD50 values for rabbits at levels of >3,700 mg/kg for a group of triaryl phosphates, >5,000 mg/kg for dibutyl phenyl phosphate, 5,000 mg/kg for both asymmetrical and symmetrical triaryls, and >3,100 mg/kg for tributyl phosphate. This study looked at structural activity relationships for the organophosphate esters. 

The prevalence of 17-ethynyl carbinols among the orally active 19-nor progestins can lead to the impression that this is a necessary group for activity. The good potency shown by a compound that possesses the 17-hydroxy 17-acetyl moiety more characteristic of the 19-methyl progestins indicates that the structure-activity relationship is not quite that narrow. One... 

---