Structure-inhibitory potency relationship

The analyses for structure-inhibitory potency relationships indicated that the improvement of inhibitory potency against plant PDHc required an optimal combination of R R, R, and Y . As shown in Scheme 7.4, when 2,4-Cl2 as Y are kept constant, inhibitory potency of the compound could be greatly enhanced by the chemical modification of R, R and R in the phosphoms-containing moiety. Especially the conversion of phosphonate esters to their salts could make great improvement in inhibitory potency against plant PDHc. Thus IIB-2 was found to exhibit the best inhibitory potency against rice PDHc. 

The effects of harmine, harmaline, and other harmala alkaloids on the contractions induced in the vascular smooth muscle of rabbit aorta and intestinal smooth muscle of taenia isolated from guinea-pig caecum were examined. The order of inhibitory potency was 6-methoxyharman = harmine > harmaline = 2-methylharmine = harmane > 6-methoxyharmalan > harmalol = harmol for contractions induced by high K+1 in aorta and taenia and by carbachol in taenia. The order of inhibitory potency for contractions induced by noradrenaline in the aorta were 2-methylharmine > 6-methoxyharman > 6-methoxyharmalan - harmol = harmalol = harmane > harmine > harmaline. The results suggest that harmaline inhibits the contractile response of rabbit aorta and guinea-pig taenia via inhibition of different types of Ca+2 channel. The structure-activity relationship indicates that the potency and selectivity of the inhibitory effects on these channels are varied by modification of the structure within this alkaloid series [270]. 

To explore structure-function relationships and optimize their activities, NeuAc-substituted acrylamide polymers were prepared with a variety of appended functional groups (Fig. 22) [99]. These studies generated polymers with very high inhibitory potencies toward HA. For example, an acrylamide copolymer substituted with 10% benzylamine and 20% NeuAc residues had a Ki of 0.6 nM [100]. Both the chelate effect and steric stabilization were mechanisms suggested to contribute to the potent activity of this and related materials (Fig. 5). The NeuAc-substituted acrylamide... 

The tyrosinase inhibitory potency of these compounds was also evaluated by the authors and attempts were made to justify their structure-activity relationships [52], Their inhibitory potential is shown in Table 3. Compound 58 was foimd to be the most potent (IC50 = 3.21 [jlM), while other compounds demonstrated moderate to potent inhibitions [52]. It was reported that the substitution of functional group(s) at the C-2 and C-3 positions and the presence of the - CH2OH group play a vital role in the potency of these compounds. Compound 58 can act as a potential lead molecule to develop new drugs for the treatment of hyperpigmentation associated with the high production of melanocytes [52]. 

The identification and characterization of the two isoforms of MAO on the one hand and the synthesis of the specific inhibitors of MAO A and of MAO B chlorgyline and selegiline, respectively, on the other hand, prompted structure-activity relationship studies in order to find more specific and efficacious inhibitors for therapeutic use. These studies revealed that one of the most important determinants of the inhibitory potency of propargylamine analogs as MAO B inhibitors was their p a the optimum value being in the vicinity of 6.222V. 

A number of studies have defined the structure-activity relationships (SARs) of the thiouracils and other related compounds as inhibitors of outer ring deiodinase (70). The C2 thioketo/thioenol group and an unsubstituted Ni position are essential for activity. The enolic hydroxyl group at C4 in PTU and the presence of alkyl group at C5 and Ce enhance the inhibitory potency. 

Fig. 7.10 Concentration-dependent inhibition of binding of IgE antibodies specific for tertiary and quaternary methyl (mainly) and ethyl eunino groups by neuromuscular blocking drugs. Side-by-side quantitative comparisons of inhibitory potencies of rocuronium and alcuronium with six other neuromuscular blocking drugs. Refer to Table 7.11 for the precise quantitative relationships. The dashed line indicates 50 % inhibition. From Pham NH et al. Studies on the mechanism of multiple drug allergies. Structural basis of drug recognition. J Immunoassay Immunochem. 2001 22 47. Reprinted with permission from Taylor Francis...

Quantitative Structure-Activity Relationships Mathematical (Empirical) Model - Employing the method of Free and Wilson, Beasley and Purcell have reported the successful prediction of the butyriicholinesterase inhibitory potency of l-decyl-3-(N-ethyl-N-methylcarbamoyl)piperidine hydrobromide. Three years after the predicted biochemical response was published, this compound was synthesized and evaluated biochemically. The observed response was found to be quantitatively near the predicted value. ... 

WIN 57294 137 is a potent inhibitor of DNA gyrase it is both clastogenic and mutagenic, which precluded its development as a human anti-infective agent [193]. This compound was subsequently found to possess moderate topo II inhibitory activity ( 50=7.6 pM). Structure activity relationship studies of WIN 57294 137 resulted in the discovery that the 3-CO2H group was not a requisite for topo II potency for 138, ( 50= 17 pM) [194]. A conformationally rigid quinolone derivative 139 has been reported to display better topo II potency ( 50=2.77 pM) [195]. 

X-Ray data are also useful for molecular modeling of the biological potency. Thus, the X-ray data of benzazocine 12 were manipulated in connection with its inhibitory effect on 17/3-hydroxysteroid dehydrogenase type 3 to support structure-activity relationship considerations <2006BML1532>. 

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