QSAR studies on structurally similar 2-(4-methanesulfonylphenyl)pyran-4-ones as selective COX-2 inhibitors: a Hansch approach

QSAR analysis based on classical Hansch approach was adopted on two recently reported novel series of 2-phenylpyran-4-ones as selective cyclooxygenase-2 (COX-2) inhibitors. The 6-methyl derivatives of title compounds bifurcate as 3-phenoxypyran-4-ones (subset A) and 3-phenylpyran-4-ones (subset B) among series 1. Series 2 consists of 5-chloro derivatives of title compounds. Various regression equations were derived to study the influence of phenoxy and phenyl ring substituents of series 1 compounds on COX-2, COX-1 and selective COX-2 over COX-1 inhibitory activity. The best triparametric equation derived for 36 compounds of series 1 explains the hydrophobic, electronic and steric requirements for improved COX-2 inhibitory activity. QSAR model derived to explore the selective COX-2 over COX-1 inhibition showed that selectivity could be influenced by size and lipophilicity of substituents. The size of the first atom of 2 substituents appears to have negative effect on selectivity, whereas highly polar 3 substituents at R are favorable for improved selectivity. QSAR investigations on series 2 compounds revealed some interesting correlation of COX-2 inhibitory activity with calculated physicochemical properties of whole molecules. The positive logP confirms the hydrophobic interaction of series 2 compounds with COX-2 enzyme. The positive MR term indicates that an overall increase in size and polarizabilty of the molecules increases COX-2 inhibitory activity. The positive contribution of structural variable suggests biphenyl analogs are extremely potent COX-2 inhibitors.     

Quantitative structure-activity relationship study on affinity profile of a series of 1,8-naphthyridine antagonists toward bovine adenosine receptors

The affinity profiles for the bovine adenosine receptors, A(1) and A(2A), of a series of 1,8-naphthyridine derivatives were quantitatively analyzed using physicochemical and structural parameters of the substituents, present at varying positions of the molecules. The derived significant correlation, for bovine A(1) receptor, suggested that a R(1) substituent having a higher van der Waals volume, a R(2) substituent being a hydrogen-bond donor and a R(3) substituent able to transmit a higher field effect are helpful in augmenting the pK(i) of a compound. Similarly the study, pertaining to bovine A(2A) receptor, revealed that a less bulky substituent at R(2) and a strong electron-withdrawing substituent at R(3) are desirable in improving the binding affinity of a compound while substituents at R(1) remain insignificant to any interaction.     

Microbiological hydroxylation of androst-1,4-dien-3,17-dione by Neurospora crassa

Nine hydroxy-derived androstadiene compounds were isolated from the fermentation broth of Neurospora crassa when incubated in the presence of androst-1,4-dien-3,17-dione (ADD; I) for 7 days. Hydroxylations at 6β, 7β, 11α, 14α- positions and 17-carbonyl reduction of the substrate were the characteristics observed in this biotransformation. Their structures were determined by spectroscopic methods as 17β-hydroxyandrost-1,4-dien-3-one (II), 14α-hydroxyandrost-1,4-dien-3,17-dione (III), 6β-hydroxyandrost-1,4-dien-3,17-dione (IV), 11α-hydroxyandrost-1,4-dien-3,17-dione (V), 6β,17β-dihydroxyandrost-1,4-dien-3-one (VI), 7β-hydroxyandrost-1,4-dien-3,17-dione (VII), 14α,17β-dihydroxyandrost-1,4-dien-3-one (VIII), 6β,14α-dihydroxyandrost-1,4-dien-3,17-dione (IX), and 11α,17β-dihydroxyandrost-1,4-dien-3-one (X). A new steroid substance, 6β,14α-dihydroxyandrost-1,4-dien-3,17-dione (IX), was also characterized during this study. The best fermentation condition was found to be 7-day incubation at 25°C and pH values of 5.0–6.0 in the presence of 0.05 g 100 mL^?1 of the substrate. At a concentration above 0.075 g 100 mL^?1, the biotransformation was completely inhibited.     

Quantitative structure-activity relationship study of iodinated analogues of trimetoquinol as highly potent beta 2-adrenoceptor ligands.

Trimetoquinol and its derivatives, reported to be highly potent beta 2-adrenoceptor (beta 2-AR) and site-selective thromboxane A2/prostaglandin H2 (TP) receptor ligands are subjected to quantitative structure-activity relationship (QSAR) study. From the significant correlation equation, obtained between the binding affinity, pKi (beta 2-AR) and the substitutional physicochemical parameters such as molar refraction, (MR), hydrophobic constant, (pi) and resonance parameter, (R), the receptor binding interactions associated with the varying sites of these compounds are discussed. The QSAR study has also explored the possibilities of having the analogous of improved binding affinities in future synthetic efforts. Likewise, the ratio of binding affinities, expressed as-log[Ki(beta 2-AR)/Ki alpha(TP)] related to two receptors are significantly correlated with MR and pi of the substituents and the relationship may, therefore, be helpful in developing the agents of greater selectivity on beta 2-AR versus TP receptor and vice versa.     

A quantitative structure-activity relationship study of novel, potent, orally active, selective VEGFR-2 and PDGFRalpha tyrosine kinase inhibitors: derivatives of N-phenyl-N'-{4-(4-quinolyloxy)phenyl}urea as antitumor agents

The tyrosine kinase inhibitory action of the derivatives of N-Phenyl-N'-{4-(4-quinolyloxy)phenyl}urea is quantitatively analyzed using multiple regression analysis. The analysis has helped to ascertain the role of different substituents in explaining the observed inhibitory actions of these compounds for two receptors, namely vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor alpha (PDGFRalpha). From a derived significant correlation equation for inhibition of VEGFR-2, it was concluded that a less hydrophobic molecule with ortho-substituent(s), exerting less steric hindrance and para-substituent devoid of hydrogen-bond acceptor property augment the inhibition action. Besides, a 3-substituent transmitting a higher negative field effect is advantageous to improve the pIC(50) value of a compound. The correlation equation, derived for the inhibition of PDGFRalpha, has revealed that a less hydrophobic molecule, having a 3-substituent which transmits a more negative resonance effect, is helpful in raising its activity. Likewise, in the middle phenyl ring, absence of a fluoro substituent augments the inhibitory activity. Based on derived QSAR equations pertaining to VEGF-2 and PDGFalpha receptors, the drawn guidelines for selection of substituents, may be used to synthesize potent compounds in future.     

Quantitative structure-activity relationship study of 5-iodo- and diaryl-analogues of tubercidin: inhibitors of adenosine kinase

The adenosine kinase inhibitory (AKI) activity of 5-iodo and diaryl analogues of tubercidin is quantitatively analyzed using Fujita-Ban and Hansch type analyses. The Fujita-Ban analysis being a non-parametric approach assigned the highest contribution to Cl at the X-position, C6H4-4-Cl, C6H5, 2-furanyl and I at the Y-position and CH2NH2 and CH3 at the Z-position. In addition, a OH substituent at the C-position also emerged as a better choice possibly due to its engagement in hydrogen bonding with some active site function. Thus a compound having Cl, C6H4-4-Cl, CH2NH2 and OH respectively at X-, Y-, Z- and C-positions is predicted to have a potency nearly 1.5 orders of magnitude higher than the most potent compound of the parent data set. The Hansch type analysis, on the other hand, is a parametric approach and is carried out on two sub-sets of original compounds. This sub-division is based on size and nature of the substituents present at the X- and Y-positions. For the compounds in the first sub-set the derived significant correlation equation suggested that the substituent at the Y-position exhibiting a higher field effect and a substituent such as Cl and CH2NH2 at X- and Z-positions, respectively, are important for a compound to show increased AKI activity. Thio/alkylthio at X and CH2OCH3 at Z, on the other hand, lead to a detrimental effect. Similarly for the compounds in the second subset, the derived significant correlation equation showed that a substituent at the X-position having a higher negative field effect, a substituent at the Y-position having bulky groups and the C-position occupied by a OH group are essential for enhancement of the activity of a compound.     

QSAR of adenosine A3 receptor antagonist 1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives using chemometric tools

Considering the potential of selective adenosine A3 receptor subtype ligands in the development of prospective therapeutic agents, an attempt has been made to explore physicochemical requirements of 1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives for A3 receptor binding. In this study, lipophilicity (logP), physicochemical substituent constants (pi, MR, sigma p) of phenyl ring substituents, and Wang-Ford charges of common atoms of the quinoxaline nucleus (calculated from molecular electrostatic potential surface of energy-minimized geometry using AM1 technique) were used as independent variables along with suitable dummy parameters. The best multiple linear regression (MLR) equation obtained from factor analysis (FA-MLR) as the preprocessing step could explain and predict 72.6% and 65.3%, respectively, of the variance of the binding affinity. The same equation also emerged as the best equation in the population of 100 equations obtained from genetic function approximation (GFA-MLR). The results suggested that presence of an electron-withdrawing group at the para position of the phenyl ring would be favorable for the binding affinity. Again, the presence of a nitro group at position R1 increases the binding affinity. When factor scores were used as predictor variables in the principal component regression analysis, the resultant model showed 78.6% explained variance and 63.1% predicted variance. The best equation derived from G/PLS could explain and predict 74.4% and 64.8%, respectively. The results have suggested the importance of Wang-Ford charges of atoms C15 and C19, apart from positive contributions of electron-withdrawing para substituents of the variance of the phenyl ring and nitro group at the R1 position.     

Synthesis and characterization of nickel(II) and copper(II) complexes with tetradentate Schiff base ligands

The 1:1 condensation of 1,2-diaminopropane and 1-phenylbutane-1,3-dione at high dilution gives a mixture of two positional isomers of terdentate mono-condensed Schiff bases 6-amino-3-methyl-1-phenyl-4-aza-2-hepten-1-one (HAMPAH) and 6-amino-3,5-dimethyl-1-phenyl-4-aza-2-hexen-1-one (HADPAH). The mixture of the terdentate ligands has been used for further condensation with pyridine-2-carboxaldehyde or 2-acetylpyridine to obtain the unsymmetrical tetradentate Schiff base ligands. The tetradentate Schiff bases are then allowed to react with the methanol solution of copper(II) and nickel(II) perchlorate separately. The X-ray diffraction confirms the structures of two of the complexes and shows that the condensation site of the diamine with 1-phenylbutane-1,3-dione is the same.     

First QSAR report on FSH receptor antagonistic activity: quantitative investigations on physico-chemical and structural features among 6-amino-4-phenyltetrahydroquinoline derivatives

A quantitative attempt has been made to correlate the structure-activity relationship (SAR) among the recently reported 6-amino-4-phenyltetrahydroquinoline derivatives as antagonists for the Gs-protein-coupled human follicle-stimulating hormone (FSH) receptor. The compounds used for the present study have been reported to show high antagonistic efficacy in vitro using a CHO-hFSHR(luc) assay. Our QSAR investigations revealed a hydrophobic type of interactions between these ligands and the FSH receptor, hence confirming the presence of a lipophilic pocket on the active site of the target structure. The positive coefficient of ClogP variable in our derived QSAR model suggests that more hydrophobic ligands are crucial for their FSH receptor antagonistic efficacy. In exploring the structural requirements among these congeners, we found an amide linkage as conducive to their FSH receptor antagonistic activity. Also, an unsubstituted 4-phenyl ring of the tetrahydroquinoline scaffold is favorable for their FSH receptor antagonistic activity. The results discussed herein could be useful in understanding the nature of interactions of these newly identified ligands as FSH receptor antagonists and in designing more potent ligands based on this novel 6-amino-4-phenyltetrahydroquinoline scaffold.     

Toussaintines A-E: antimicrobial indolidinoids, a cinnamoylhydrobenzofuranoid and a cinnamoylcyclohexenoid from Toussaintia orientalis leaves

Toussaintine A (N-cinnamoyl-5,6-dehydro-4-hydroxyindolidin-2,7-dione), toussaintine B (N-cinnamoyl-5,6-dehydro-4,7-dihydroxyindolidin-2-one), toussaintine C (N-cinnamoyl-5,6-dehydro-4-hydroxyindolidin-7-one), toussaintine D (N-cinnamoyl-2-amino-4-hydroxy-7-oxo-2,3,8,9-tetrahydrobenzofuran) and toussaintine E (N-cinnamoyl-1-acetoxymethyl-2-amino-1-hydroxycyclox-5-en-4-one) were isolated as antibacterial and antifungal constituents of the leaves of Toussaintia orientalis Verdc. (Annonaceae) and their structures established from analysis of spectroscopic data. The compounds belong to a series of variously cyclized aminocinnamoyl tetraketide derivatives, showing the importance of rarely occurring Annonaceae species as sources of structurally diverse natural products.     

Synthesis,structure-activity relationship and in vitro evaluation of coelenterazine and coelenteramine derivatives as inhibitors of lipid peroxidation

Coelenterazine (2-p -hydroxybenzyl-6-(3'-hydroxyphenyl)-8-benzyl-3,7-dihydroimidazolo[1,2-a]pyrazin-3-one, CLZn) and coelenteramine (2-amino-3-benzyl-5-(4'-hydroxyphenyl)-1,4-pyrazine CLM), first described as luciferin and etioluciferin, respectively, of bioluminescent systems in marine organisms are endowed with antioxidant properties. This study was aimed at understanding the structural basis of their chain-breaking properties and at designing new compounds with improved antioxidative properties. For this, a series of 2-amino-1,4-pyrazine derivatives and their related imidazolopyrazinones were synthesised and examined for their capacity to inhibit lipid peroxidation in linoleate micelles subjected to the peroxidizing action of AAPH. Structure-activity relationship studies indicated that the reduction of the peroxidation rate by CLM is mainly determined by the concomitant presence of 5-p-hydroxyphenyl and 2-amino groups in para position. The lipophilic character of substituents also affected this effect. All imidazolopyrazinones induced a lag-time before the onset of the peroxidation process. The hetero-bicyclic imidazolopyrazinone moiety appears as the main contributor to this activity while phenol groups play little role in it. On the other hand, phenol groups were required for the reduction of the peroxidation rate after the lag-phase. The introduction of a supplementary p-hydroxyphenyl substituent at C₈ position did not increase chain-breaking properties. The substitution of the C₅-p-hydroxyphenyl with a catechol moiety or the introduction of a second amino group on the pyrazine ring yielded the most active compounds, superior to imidazolopyrazinones and reference antioxidants like epigallocatechin gallate, vitamin E and trolox. The strong antioxidant properties of 2,6-diaminopyrazines are not dependent on the presence of hydroxyl groups indicating that their reaction mechanism differs from that of 2-amino-1,4-pyrazine derivatives.     

Design and synthesis of 6-amino-1,4-oxazepane-3,5-dione derivatives as novel broad spectrum anticonvulsants

Based on the structural estimations of the typical anticonvulsant drugs, a series of 6-amino-1,4-oxazepane-3,5-dione derivatives, novel structures of 7-membered heterocyclic imides, which were hybridized with pharmacophores such as cyclic imide and N-CO-C-N group in their molecule were designed and synthesized. Their anticonvulsant activities were evaluated by the maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (PTZ) tests. Almost all the designed compounds except 1c and 1f showed comparable anticonvulsant activities in at least one of the anticonvulsant tests. Moreover, some of the tested compounds exhibited moderate anticonvulsant activities in both MES and PTZ tests. From these results, 6-amino-1,4-oxazepane-3,5-dione derivatives could be recommended as novel structures of broad spectrum anticonvulsants.     

A quantitative structure-activity relationship study of novel,potent, orally active,selective VEGFR-2 and PDGFRα tyrosine kinase inhibitors: Derivatives of N-Phenyl-N′-{4-(4-quinolyloxy)phenyl}urea as antitumor agents

The tyrosine kinase inhibitory action of the derivatives of N-Phenyl-N′-{4-(4-quinolyloxy)phenyl}urea is quantitatively analyzed using multiple regression analysis. The analysis has helped to ascertain the role of different substituents in explaining the observed inhibitory actions of these compounds for two receptors, namely vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor α (PDGFRα). From a derived significant correlation equation for inhibition of VEGFR-2, it was concluded that a less hydrophobic molecule with ortho-substituent(s), exerting less steric hindrance and para-substituent devoid of hydrogen-bond acceptor property augment the inhibition action. Besides, a 3-substituent transmitting a higher negative field effect is advantageous to improve the pIC₅₀ value of a compound. The correlation equation, derived for the inhibition of PDGFRα, has revealed that a less hydrophobic molecule, having a 3-substituent which transmits a more negative resonance effect, is helpful in raising its activity. Likewise, in the middle phenyl ring, absence of a fluoro substituent augments the inhibitory activity. Based on derived QSAR equations pertaining to VEGF-2 and PDGFα receptors, the drawn guidelines for selection of substituents, may be used to synthesize potent compounds in future.     

Influence of the terminal amide fragment geometry in some 3-arylideneindolin-2(1H)-ones on their 5-HT1A/5-HT2A receptor activity

Several 1,4-disubstituted arylpiperazine derivatives of 3-arylideneindolin-2(1H)-one (Z and E isomers) were tested for their 5-HT1A and 5-HT2A receptor activity in vitro and in vivo. It was shown that introduction of 3-arylidene substituents to indolin-2(1H)-one moiety allowed to change the mixed 5-HT1A/5-HT2A receptor ligands to 5-HT2A ones with antagonistic in vivo activity.     

Quantitative structure-activity relationship study of novel alpha1a-selective adrenoceptor antagonists

Two series of compounds were recently reported as novel alpha1a-selective adrenoceptor antagonists. In the first series, a dihydropyrimidone moiety is attached to a 4-phenyl piperidine containing side chain, while in the second, it is linked to a 4-substituted phenyl piperazine containing side chain. These compounds having potential for the treatment of benign prostatic hyperplasia, a urological disorder in the older age male population, were subjected to a quantitative structure-activity relationship study. The analysis has helped to ascertain the role of different substituents in explaining the observed binding potencies of these analogues. In the first category of compounds, three sites R1, R2, and X were varied and from the quantitative structure-activity relationship, it emerged that X- and R1-substituents having respectively, the high values of field and resonance effects may lead to more potent alpha1a-antagonists. The substituent of R2, being either CH3 or C2H5, does not add to improve the activity and thus the site, at present, becomes redundant. This site may, however, be explored for some additional substituents in future. In the second series of compounds, the phenyl ring, linked to a piperazine moiety at the end of a side chain, was substituted with various groups onto different positions. From derived significant correlations, it appeared the less polar and/or bulky substituents at the meta- and para-positions and a more hydrophobic substituent at the para-position are advantageous.     

3D-QSAR study indicates an enhancing effect of membrane ions on psychiatric drugs targeting serotonin receptor 5-HT1A

Antidepressants and antipsychotics are psychiatric agents used for the treatment of various types of psychiatric diseases. Although currently among the most commonly prescribed drugs, their effectiveness and adverse effects are the topic of many studies and controversial claims. Here we generate QSAR models based on compounds series including 20 drugs recommended for two critical psychiatric diseases: depression and schizophrenia and we use these QSAR models to predict the biological activity of these 20 antidepressants and antipsychotics. We establish the membrane ions' contributions (sodium, potassium, calcium and iron) mediated by water to the antagonism of these drugs at the 5-HT1A receptor. The reliability of our QSAR models in predicting compounds activity is indicated by significant values for cross-validated correlation q2 (0.60-0.76) and fitted correlation r2 (0.96-0.98) coefficients. Our results indicate that potassium, calcium and iron play a key role for the antagonistic activity of drugs at the 5-HT1A receptor. Moreover, based on the established QSAR equations, we analysed 24 new escitalopram derivatives as possibly improved antidepressants targeting the 5-HT1A receptor. We identified that the presence of methyl groups and hydrogen atoms improves antidepressant activity while the simultaneous presence of ethyl, propyl or halogens decreased drastically antidepressant activity at the 5-HT1A site.     

The degradation of beta-sitosterol by Pseudomonas sp. NCIB 10590 under aerobic conditions

The bacterial degradation of beta-sitosterol by Pseudomonas sp NCIB 10590 has been studied. Major biotransformation products included 24-ethylcholest-4-en-3-one, androsta-1,4-diene-3,17-dione, 3-oxochol-4-en-3-one-24-oic acid and 3-oxopregn-4-en-3-one-20-carboxylic acid. Minor products identified were 26-hydroxy-24-ethylcholest-4-en-3-one, androst-4-ene-3,17-dione, 3-oxo-24-ethylcholest-4-en-26-oic acid, 3-oxochola-1,4-dien-3-one-24-oic acid, 3-oxopregna-1,4-dien-3-one-20 carboxylic acid and 9 alpha-hydroxyandrosta-1,4-diene-3,17-dione. Studies with selected inhibitors have enabled the elucidation of a comprehensive pathway of beta-sitosterol degradation by bacteria.