A review on quantitative structure-activity relationships (QSARs) of natural and synthetic antioxidants compounds

During the last decade an increasing number of reports describe the roles of active oxygen species in the development or exacerbation of various kinds of diseases. Antioxidants are of great interest because of their involvement in important biological and industrial processes. They have been found to possess anticancer, anti-cardiovascular, anti-inflammatory and many other activities. Many attempts have been made to elucidate the QSAR of antioxidants by using different physicochemical parameters. Unfortunately the limited number of antioxidants and the unavailable sigma Hammett values of complex substituents did not lead to significant results in regression analysis. The redox potentials are well correlated to the antioxidant activities. In this report we will attempt to collect and discuss all the published results concerning the QSAR research on natural and synthetic antioxidants compounds.     

Secondary structure peptide mimetics: design, synthesis, and evaluation of beta-strand mimetic thrombin inhibitors

Constrained dipeptide mimetic templates were designed to mimic the secondary structure of peptides in a beta-strand conformation. Two templates corresponding to the D-Phe-Pro portion of the thrombin inhibitor D-Phe-Pro-ArgCH2Cl were synthesized and converted into nine alpha-ketoamide and alpha-ketoheterocycle inhibitors of thrombin. Additionally, a template corresponding to L-Phe-Pro was synthesized and converted to a thrombin inhibitor. The in vitro inhibition of thrombin by these compounds was determined, and those corresponding to the D-Phe-Pro were found to be more potent inhibitors than the L-Phe-Pro mimetic. The alpha-ketoamides were found to be more potent than the alpha-ketoheterocycles but had much slower on rates. By comparison of a series of alpha-ketoamide analogues, it is apparent that the there is a preference for binding of bulky hydrophobic substituents in the P' portion of the thrombin active site. Three of the inhibitors (MOL098, MOL144, and MOL174) were screened against a series of coagulation and anticoagulation enzymes and found to be selective for inhibition of the coagulation enzymes. Two of the inhibitors were tested in in vitro models of intestinal absorption and found to have low absorption potential. The compounds were then tested in vivo in both rats and primates, and one of them (MOL144) was approximately 25% absorbed in both species. This study has delineated the synthesis of constrained dipeptide beta-strand mimetics and validated the potential for compounds of this type as potent thrombin inhibitors and possible drug leads.     

Quantitative structure-activity relationship of human neutrophil collagenase (MMP-8) inhibitors using comparative molecular field analysis and X-ray structure analysis.

A set of 90 novel 2-(arylsulfonyl)-1,2,3, 4-tetrahydroisoquinoline-3-carboxylates and -hydroxamates as inhibitors of the matrix metalloproteinase human neutrophil collagenase (MMP-8) was designed, synthesized, and investigated by 3D-QSAR techniques (CoMFA, CoMSIA) and X-ray structure analysis. Docking studies of a reference compound are based on crystal structures of MMP-8 complexed with peptidic inhibitors to propose a model of its bioactive conformation. This model was validated by a 1. 7 A X-ray structure of the catalytic domain of MMP-8. The 3D-QSAR models based on a superposition rule derived from these docking studies were validated using conventional and cross-validated r2 values using the leave-one-out method, repeated analyses using two randomly chosen cross-validation groups plus randomization of biological activities. This led to consistent and highly predictive 3D-QSAR models with good correlation coefficients for both CoMFA and CoMSIA, which were found to correspond to experimentally determined MMP-8 catalytic site topology in terms of steric, electrostatic, and hydrophobic complementarity. Subsets selected as smaller training sets using 2D fingerprints and maximum dissimilarity methods resulted in 3D-QSAR models with remarkable correlation coefficients and a high predictive power. This allowed to compensate the weaker zinc binding properties of carboxylates by introducing optimal fitting P1' residues. The final QSAR information agrees with all experimental data for the binding topology and thus provides clear guidelines and accurate activity predictions for novel MMP-8 inhibitors.     

Small molecule inhibitors of KDR (VEGFR-2) kinase: an overview of structure activity relationships

The Kinase insert Domain containing Receptor (KDR), alternatively referred to as VEGFR-2, is a receptor for Vascular Endothelial Growth Factors (VEGFs) and functions as a key regulator of angiogenesis, the process by which new capillaries are created from preexisting blood vessels. The induction of angiogenesis, or the "angiogenic switch," is a critical step in tumor progression, and inhibitors of KDR have been demonstrated both to induce tumor regression and reduce metastatic potential in preclinical models. In the last few years, medicinal chemists have expanded the kinase selectivity profile of known inhibitor classes to include KDR, and also identified novel classes of KDR inhibitors. This review presents structure activity relationships (SAR) of small molecule inhibitors of KDR, with an emphasis on the pharmacophore elements of the scaffolds employed. Binding hypotheses based on X-ray crystallographic analyses will also be described. Additionally, the efficacy of representative compounds in in vitro and in vivo models of tumor progression and angiogenesis are discussed.     

Utilization of quantitative structure-activity relationships (QSARs) in risk assessment: Alkylphenols

Alkylphenols are a class of environmentally pervasive compounds, found both in natural (e.g., crude oils) and in anthropogenic (e.g., wood tar, coal gasification waste) materials. Despite the frequent environmental occurrence of these chemicals, there is a limited toxicity database on alkylphenols. We have therefore developed a "toxicity equivalence approach" for alkylphenols which is based on their ability to inhibit, in a specific manner, the enzyme cyclooxygenase. Enzyme-inhibiting ability for individual alkylphenols can be estimated based on the quantitative structure-activity relationship developed by Dewhirst (1980) and is a function of the free hydroxyl group, electron-donating ring substituents, and hydrophobic aromatic ring substituents. We evaluated the toxicological significance of cyclooxygenase inhibition by comparison of the inhibitory capacity of alkylphenols with the inhibitory capacity of acetylsalicylic acid, or aspirin, a compound whose low-level effects are due to cyclooxygenase inhibition. Since nearly complete absorption for alkylphenols and aspirin is predicted, based on estimates of hydrophobicity and fraction of charged molecules at gastrointestinal pHs, risks from alkylphenols can be expressed directly in terms of "milligram aspirin equivalence," without correction for absorption differences. We recommend this method for assessing risks of mixtures of alkylphenols, especially for those compounds with no chronic toxicity data.     

Three-dimensional quantitative structure-activity relationships of cyclo-oxygenase-2 (COX-2) inhibitors: a comparative molecular field analysis

The three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using comparative molecular field analysis (CoMFA) was applied to an extensive series of 305 varied diarylheterocyclic derivatives known as COX-2 selective inhibitors. X-ray crystal structure of COX-2 bound with SC-558, a selective COX-2 inhibitor, was used to derive the putative bioactive conformation of these inhibitors. Five statistically significant models were obtained from the randomly constituted training sets (229 compounds) and subsequently validated with the corresponding test sets (76 compounds). The best predictive model (n = 229, q(2) = 0.714, N = 8, r(2) = 0.905, s = 0.291, F = 261.545) was selected for further comparison of the CoMFA contour maps obtained for steric, electrostatic, and lipophilic fields with the enzyme structure. The high level of compatibility with the COX-2 enzyme topology shows the great accuracy of this model that can predict inhibitory activities for a wide range of compounds and offers important structural insight into designing novel antiinflammatory drugs prior to their synthesis.     

Quantitative structure-activity relationships (QSARs) for substrates of human cytochromes P450 CYP2 family enzymes.

The results of quantitative structure-activity relationship (QSAR) studies on substrates of human CYP2 family enzymes are reported, together with those of a small number of CYP2A6, CYP2C19 and CYP2D6 inhibitors. In general, there are good correlations (R = 0.90-0.99) between binding affinity (based on Km or KD values) and various parameters relating to active site interactions such as hydrogen bonding and pi-pi stacking. There is also evidence for the role of compound lipophilicity (as determined by either log P or log D7.4 values) in overall substrate binding affinity, and this could reflect the desolvation energy involved in substrate interaction within the enzyme active site. It is possible to estimate the substrate binding energy for a given P450 from a combination of energy terms relating to hydrogen bonding, pi-pi stacking, desolvation and loss in rotatable bond energy, which agree closely (R = 0.98) with experimental data based on either Km or KD values. Consequently, it is likely that active site interactions represent the major contributory factors to the overall binding affinities for human CYP2 family substrates and, therefore, their estimation is of potential importance for the development of new chemical entities (NCEs) as this can facilitate an assessment of likely metabolic clearance.     

Polychlorinated biphenyls: correlation between in vivo and in vitro quantitative structure-activity relationships (QSARs)

The in vivo quantitative structure-activity relationships (QSARs) for several polychlorinated biphenyls (PCBs) were determined in the immature male Wistar rat. The ED25 and ED50 values for hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) induction as well as for body weight loss and for thymic atrophy were determined for nine PCB congeners and 4'-bromo-2,3,4,5-tetrachlorobiphenyl. The most active compounds were the coplanar PCB congeners, 3,3',4,4',5-penta- and 3,3',4,4',5,5'-hexachlorobiphenyl; for example, their ED50 values for body weight loss were 3.25 and 15.1 mumol/kg, respectively. The in vivo toxicity of the coplanar PCB, 3,3',4,4'-tetrachlorobiphenyl, was significantly lower (ED50 for body weight loss = 730 mumol/kg) than the values observed for the more highly chlorinated homologs, and this was consistent with the more rapid metabolism of the lower chlorinated congener. The dose-response biologic and toxic effects of several mono-ortho-chloro-substituted analogs of the coplanar PCBs, including 2,3,4,4'5-, 2,3,3',4,4'-, 2',3,4,4',5- and 2,3',4,4',5-penta-, 2,3,3',4,4',5- and 2,3,3',4,4',5'-hexachlorobiphenyl were also determined, and members of this group of compounds were all less toxic than 3,3',4,4',5-penta and 3,3',4,4',5,5'-hexachlorobiphenyl. There was a good rank order correlation between the in vivo QSAR data and the in vitro QSARs for PCBs that were developed from their relative receptor binding affinities and potencies as inducers of AHH and EROD in rat hepatoma H-4-II E cells in culture. These results are consistent with the proposed receptor-mediated mechanism of action for PCBs. In addition, for this series of halogenated biphenyls there was a linear correlation between their in vivo toxicity in rats and their in vitro monooxygenase enzyme induction results. Assuming that the in vivo toxic responses in the rat are representative toxic responses to PCBs, then these results support the predictive utility of the in vitro bioassay with rat hepatoma H-4-II E cells as a short-term test system for the potential toxicity of this class of halogenated aryl hydrocarbons.     

Quantitative structure-activity relationships (QSARs) within cytochromes P450 2B (CYP2B) subfamily enzymes: the importance of lipophilicity for binding and metabolism

The results of qualitative structure-activity relationship (QSAR) analysis are reported for several series of compounds which act as substrates for mammalian CYP2B subfamily enzymes, together with a homologous series of aliphatic primary amines which are known to inhibit CYP2B enzymes. It is found that the compound lipophilicity in the form of the log P value (where P is the octanol/water partition coefficient) is related, either linearly or quadratically, to equilibrium constants of inhibition (Ki), binding (Ks) or metabolism (Km) depending on the series of compounds in question. In some instances, the difference between frontier orbital energy levels (deltaE) also features in several of the log P expressions with biological activity. Also present in a small number of correlations are parameters which are likely to be related to logP: namely, Rm, which is the partitioning factor derived from thin layer chromatography (TLC) retention times, and also the compound molecular weight (Mr). All of these three parameters ((log P, Rm and Mr) are thought to be related to the compound's ability to desolvate the P450 active site when they bind to the enzyme. Although the linear relationships between lipophilicity and CYP2B-related activity point to a major role for desolvation of the enzyme binding site in the overall interaction, it is noted that there may be an optimal log P value displayed by preferred substrates as shown by parabolic relationships with this lipophilic parameter. In addition, there is a remarkable similarity in the coefficients for the log P term of any QSAR expression, which suggests that the hydrophobicity of CYP2B active sites may be broadly equivalent between the various mammalian species.     

Endotoxins: relationships between structure, function, and activity

Molecules of endotoxin (lipopolysaccharides, LPS), forming a unique molecular class with peculiar physico-chemical properties, impart a very important role in the formation and function of the outer membrane (OM). The latter is strictly asymmetric with the LPS monolayer forming the outer leaflet and the phospholipid (PL) monolayer forming the inner leaflet. Thus, the OM builds a functional lipid environment for the OM proteins (Omp's, porins) and the LPS layer is the first locus of interaction of the bacterial cells with components of the host's immune system,. Therefore its physical state and biochemical parameters (such as the fluidity of the lipid A acyl chains and the backbone charge density) essentially influence the defense of bacteria against the attack of the human immune systems such as the complement and antimicrobial peptides/proteins. LPS, released from the bacterial cell, is responsible for a variety of biological effects which can be ascribed to the unique structural features of LPS- the three-dimensional supramolecular structure and the intramolecular conformation - which are essential determinants of the bioactivity of endotoxins. Here, the physico-chemical parameters which are important on the one side for the function of the OM and on the other side for the activity of isolated LPS are reviewed.     

Structure-activity relationships of new A,D-ring modified steroids as aromatase inhibitors: design, synthesis, and biological activity evaluation

Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cancer. New A,D-ring modified steroid analogues of formestane and testolactone were designed and synthesized and their biochemical activity was investigated in vitro in an attempt to find new aromatase inhibitors and to gain insight into their structure-activity relationships (SAR). All compounds tested were less active than formestane. However, the 3-deoxy steroidal olefin 3a and its epoxide derivative 4a proved to be strong competitive aromatase inhibitors (K(i) = 50 and 38 nM and IC50 = 225 and 145 nM, respectively). According to our findings, the C-3 carbonyl group is not essential for anti-aromatase activity, but 5alpha-stereochemistry and some planarity in the steroidal framework is required. Furthermore, modification of the steroidal cyclopentanone D-ring, by construction of a delta-lactone six-membered ring, decreases the inhibitory potency. From the results obtained, it may be concluded that the binding pocket of the active site of aromatase requires planarity in the region of the steroid A,B-rings and the D-ring structure is critical for the binding.     

Stimulus properties of benzodiazepines: correlations with binding affinities,therapeutic potency,and structure activity relationships (SAR)

Using a two-lever operant choice task, rats were trained to discriminate diazepam (3.0 mg/kg) from saline under a fixed-ratio 10 (FR10) schedule of reinforcement. Once the discrimination was learned, generalization studies were conducted using various doses of 17 benzodiazepine derivatives. The diazepam stimulus generalized in a dose-related manner to each of these compounds. ED₅₀ values were compared with available data on displacing affinities (K _i values) for tritiated diazepam brain binding in man, and with human therapeutic potency. A significant correlation (r=0.88, n=9) was found between benzodiazepine binding affinities and ED50 values derived from the diazepam stimulus generalization assay. A significant correlation (r=0.92, n=10) was also found between drug discrimination ED₅₀ values and human therapeutic potencies. Finally, the benzodiazepine structure activity relationships generated from the drug discrimination studies closely paralleled the known structure activity relationships for these agents. The results provide further evidence that benzodiazepines exert their pharmacological effects through an interaction with benzodiazepine receptors.     

Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 3. Structure activity relationships at C3(1,2)

The identification of indeno[1,2-c]pyrazol-4-ones as inhibitors of cyclin-dependent kinases (CDKs) has led to the discovery of a series of novel and potent compounds. Herein, we report the effects of substitutions at C3 of the indeno[1,2-c]pyrazol-4-one core with alkyls, heterocycles, and substituted phenyls. Substitutions at the para position of the phenyl ring at C3 were generally well-tolerated; however, larger groups were generally inactive. For alkyls directly attached to C3, longer chain substituents were not tolerated; however, shorter alkyl groups and cyclic alkyls were acceptable. In general, the heterocycles at C3 gave the most potent analogues. One such heterocycle, 24j, was examined in detail and was determined to have a biological profile consistent with CDK inhibition. An X-ray crystal structure of one of the alkyl compounds, 13q, complexed with CDK2 was determined and showed the inhibitor residing in the adenosine 5'-triphosphate pocket of the enzyme.     

Pharmacological inhibitors of NAD(P)H quinone oxidoreductase, NQO1: Structure/activity relationships and functional activity in tumour cells

NAD(P)H quinone oxidoreductase (NQO1) has multiple functions in the cell including an ability to act as a detoxifying enzyme and as a protein chaperone. The latter property is particularly important in oncology as one of the client proteins of NQO1 is p53. The inhibitor, dicoumarol, is classically used to probe the biological properties of NQO1, but interpretation of enzyme function is compromised by the multiple “off-target” effects of this agent. Coumarin-based compounds that are more potent than dicoumarol as inhibitors of recombinant human NQO1 have been identified (Nolan et al., J Med Chem 2009;52:7142-56) The purpose of the work reported here is to demonstrate the functional activity of these agents for inhibiting NQO1 in cells. To do this, advantage was taken of the NQO1-mediated toxicity of the chemotherapeutic drug EO9 (Apaziquone). The toxicity of this drug is substantially reduced when the function of NQO1 is inhibited and many of the coumarin-based compounds are more efficient than dicoumarol for inhibiting EO9 toxicity. The ability to do this appears to be related to their capacity to inhibit NQO1 in cell free systems. In conclusion, agents have been identified that may be more pharmacologically useful than dicoumarol for probing the function of NQO1 in cells and tissues.