Analogue-based design, synthesis and docking of non-steroidal anti-inflammatory agents. Part 2: methyl sulfanyl/methyl sulfonyl substituted 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-ones.

A series of methyl sulfanyl/methyl sufonyl substituted 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-one were designed using analogue-based design, scaffold hopping and shape similarity matching. The designed compounds were synthesized in 2-3 steps with simple chemistry and screened by ovine cyclooxygenases (COXs) inhibitory assay and carrageenan-induced rat paw edema assay. Among the screened compounds, two compounds exhibited 100% cyclooxygenase-2 (COX-2) inhibitory potency without showing cycloxygenase-1 (COX-1) inhibition at 20 µM. The compounds also showed promising in vivo anti-inflammatory potential. A structure-activity relationship within the dataset was established by correlating the effect of aromatic ring substituent constants, structural variables and physico-chemical descriptors with in vivo anti-inflammatory activity. Molecular docking studies were also performed on the title compounds to study the binding interactions to COX-2 active site residues. The experimentally determined COX-2 inhibitory activity was found moderately correlating with binding modes predicted for compounds by Glide XP dock scoring function. The 2,3-diaryl-2,3-dihydro-1H-quinazolin-4-one pharmacophore reported herein should be a new lead for further development of novel non-steroidal anti-inflammatory agents.

Analogue-based design, synthesis and molecular docking analysis of 2,3-diaryl quinazolinones as non-ulcerogenic anti-inflammatory agents.

In our effort to identify potent gastric sparing anti-inflammatory agents, a series of methyl sulfanyl/methyl sulfonyl substituted 2,3-diaryl quinazolinones were designed by analogue-based design strategy and synthesized for biological evaluation. Subsequently, the compounds were evaluated for both cyclooxygenase inhibitions by ovine COX assay and carrageenan-induced rat paw edema assay. All the methyl sulfonyl substituted quinazolinones were exhibited promising anti-inflammatory activity. In particular, 6-bromo-3-(4-methanesulfonyl-phenyl)-2-phenyl-3H-quinazolin-4-one, 7-chloro-3-(4-methanesulfonyl-phenyl)-2-phenyl-3H-quinazolin-4-one, 3-(4-methanesulfonyl-phenyl)-2-(4-methoxy-phenyl)-3H-quinazolin-4-one and 6-bromo-3-(4-methanesulfonyl-phenyl)-2-(4-methoxy-phenyl)-3H-quinazolin-4-one emerged as the most active compounds in the series. The results of ulcerogenic activity assay suggest that these compounds are gastric safe compared to indomethacin. The molecular docking analysis was performed to understand the binding interactions of these compounds to COX-2 enzyme. The results from the present investigation suggests that 2,3-diaryl quinazolinones as a promising template for the design of new gastric safe anti-inflammatory agents, which can be further explored for potential anti-inflammatory activity.

Rationalization of physico-chemical properties of 5, 6-diarylthiazolo [3,2-b]-1, 2, 4-triazoles towards cyclooxygenase-2 (COX-2) inhibition: a QSAR approach.

Quantitative structure-activity relationship (QSAR) analysis was performed on a series of 5, 6-diarylthiazolo [3, 2-b]-1, 2, 4-triazoles to explore their possible interaction with the active amino acid residues of cyclooxygenase-2 (COX-2) enzyme. The significance of orientation and conformational rigidity of 5, 6-diarylthiazolo [3, 2-b]-1, 2, 4-triazoles for COX-2 inhibition is discerned by the spatial descriptor principle moment of inertia-X component, PMI-X. The negative contribution of PMI-X indicates the necessity of orientation of substituents towards X-axis of aromatic ring for better activity. The most common electronic interaction between the title compounds and active residues of COX-2 enzyme is corroborated well by the positive contribution of molecular dipole. The contribution of molecular dipole suggests the non-covalent, electronic interactions between 5, 6-diarylthiazolo [3, 2-b]-1, 2, 4-triazoles and binding site of COX-2 enzyme. Our findings reveal the necessity of less bulkier, less polar substituents on the parent structure for better COX-2 inhibitory activity. The limited tolerance of COX-2 enzyme active site towards the bulk of interacting molecules is evident from the negative coefficient of calculated molar refractivity (CMR) in our models.

Study on gluco-regulatory potential of glimepiride sulfonamide using in silico, in vitro and in vivo approaches.

Glimepiride sulfonamide (GS) is a drug intermediate to synthesize glimepiride (antidiabetic drug). We hypothesized that GS exerts gluco-regulatory effect because GS is comprised of the structural components of dipeptidyl peptidase-IV (DPP-IV) inhibitors sitagliptin and DPP-728and glimepiride (sulfonylurea based antidiabetic drug).We analyzed the drug-likeness and docking efficiency of GS with DPP-IV using in silico tools. Also DPP-IV inhibition assays were conducted in vitro. Gluco-regulatory potential and parameters of drug safety were evaluated on normal euglycemic and streptozotocin (STZ) induced diabetic rats. We observed strong drug-likeness and DPP-IV binding efficiency of GS. Similarly, profound DPP-IV inhibition was also observed in vitro. Studies on euglycemic and STZ induced diabetic rats revealed antidiabetic potential for GS without significant change in the studied toxicological parameters. Glimepiride sulfonamide has antidiabetic potential mainly through DPP-IV inhibition, but also through insulin stimulation and alpha-amylase inhibition.

6H-Indolo[2,3-b]quinoxalines: DNA and protein interacting scaffold for pharmacological activities.

6H-Indolo[2,3-b]quinoxaline, a planar fused heterocyclic compound exhibits a wide variety of pharmacological activities. The mechanism of pharmacological action exerted by these compounds is predominantly DNA intercalation. The thermal stability of the intercalated complex (DNA and 6H-indolo[2,3-b]quinoxaline derivatives) is an important parameter for the elucidation of anticancer, antiviral and other activities. This thermal stability of the 6H-indolo[2,3- b]quinoxaline-DNA complex depends on the type of substituents and side chains attached to the 6H-indolo[2,3- b]quinoxaline nucleus and also the orientation of the side chain towards the GC rich minor groove of the DNA. Highly active 6H-indolo[2,3-b]quinoxaline derivatives such as NCA0424, B-220 and 9-OH-B-220 have shown good binding affinity to DNA as evident from high thermal stability of compound-DNA complex. Interestingly, these compounds possessed poor inhibitory activity on topoisomerase II enzyme but have significant MDR modulating activity. This review establishes '6H-indolo[2,3-b]quinoxaline' as a valuable template for design and development of novel molecules with different biological activities.

DPP-IV inhibitory potential of naringin: an in silico, in vitro and in vivo study.

The incretin based therapies are an emerging class of antidiabetic drugs, with two categories: one is glucagone like peptide-1 (GLP-1) agonists and the other one is dipeptidyl peptidase (CD26; DPP-IV) inhibitors. However, in the DPP-IV inhibitors category only few compounds are commercially available and also have some undesirable effects. Therefore, in the present work we tried to explore a naturally occurring compound naringin for its potential DPP-IV inhibition and antidiabetic potential. It is noteworthy that this compound is abundantly present in orange peel and thus may provide cost effective treatment for diabetes, especially type 2 diabetes mellitus. In the present study, we have conducted virtual docking study and observed tight binding of naringin, as shown by higher negative values of H bond lengths, while in vitro DPP-IV inhibition assay has also shown better inhibition by naringin. In vivo study, in response to 10 days administration of 40 mg/kg of naringin twice daily to Wistar albino rats, inhibited the serum levels of DPP-IV activity, random glucose concentration with concomitant increase in insulin levels. All the comparisons were made with the standard commercially available drug sitagliptin.

QSAR investigations on benzylideneamino and phenyliminomethyl scaffolds for selective COX-2 inhibiton: a Hansch approach.

Cyclooxygenase inhibitory and selectivity profile of a combined series of thirty one aryl sulphonamide compounds possessing 4-benzylideneamino or 4-phenyliminomethyl scaffolds were subjected to QSAR study using Hansch approach. The compounds in the selected series were characterized using classical aromatic substituent constants like hydrophobicity (pi), molar refractivity (MR), Hammett electronic (sigma), electronic field effect (F), resonance effect (R), and some indicator variables encoding molecular group contributions. Statistically significant QSAR models were generated using multiple regression analysis and cross-validation tools. The derived QSAR models demonstrated that the COX-2 selectivity over COX-1 is predominantly influenced by the central core -N=C- of the diaryl system. Further, the study also indicated that the electronic properties and structural variation in the para position of the phenyl ring (B) governs the COX-2 selectivity of the title compounds. The derived results reveal the important structural features significant for improved COX-2 inhibitory activity and selectivity of these novel aryl sulfonamides.

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.

QSAR analyses of conformationally restricted 1,5-diaryl pyrazoles as selective COX-2 inhibitors: application of connection table representation of ligands.

As a part of our continuing efforts in discerning the structural and physicochemical requirements for selective COX-2 over COX-1 inhibition among the fused pyrazole ring systems, herein we report the QSAR analyses of the title compounds. The conformational flexibility of the title compounds was examined using a simple connection table representation. The conformational investigation was aided by calculating a connection table parameter called fraction of rotable bonds, b_rotR encompassing the number of rotable bonds and b_count, the number of bonds including implicit hydrogens of each ligand. The hydrophobic and steric correlation of the title compounds towards selective COX-2 inhibition was reported previously in one of our recent publications. In this communication, we attempt to calculate Wang-Ford charges of the non-hydrogen common atoms of AM1 optimized geometries of the title compounds. Owing to the partial conformational flexibility of title compounds, conformationally restricted and unrestricted descriptors were calculated from MOE. Correlation analysis of these 2D, 3D and Wang-Ford charges was accomplished by linear regression analysis. 2D molecular descriptor b_single, 3D molecular descriptors glob, std_dim3 showed significant contribution towards COX-2 inhibitory activity. Balaban J, a connectivity topological index showed a negative and positive contribution towards COX-1 and selective COX-2 over COX-1 inhibition, respectively. Wang-Ford charges calculated on C(7) showed a significant contribution towards COX-1 inhibitory activity whereas charges calculated on C(8) were crucial in governing the selectivity of COX-2 over COX-1 inhibition among these congeners.

Quantitative structure-activity relationship analysis of 2,3-diaryl indoles as selective cyclooxygenase-2 inhibitors.

Quantitative structure-activity relationship (QSAR) studies have been performed on a combined series of 2-sulfonylphenyl-3-phenyl-indoles and 2-phenyl-3-sulfonylphenyl-indoles with a common 2,3 vicinal diaryl indole scaffold, recently reported as selective COX-2 inhibitors. This study is aimed to throw light on this, special class of diaryl heterocyclic family of selective COX-2 inhibitors. A preliminary Fujita-Ban analysis on 32 compounds provided valuable insights about the role of different substituents R1 and R2 around the 2,3 vicinal diaryl rings and R3, at position-5 of the central indole moiety in explaining their in vitro COX-2 inhibitory activity. The contribution of R1, R2, R3 towards COX-2 inhibitory activity resulted in statistically significant linear multiple regression equation with r = 0.942, r(2) = 0.888, s = 0.532 and F = 7.92, q(2) = 0.516 for 29 compounds. Fujita-Ban model shows a negative contribution of SO2NH2 and SO2CH3 at the R1 position; a negative contribution of 4-Cl, 2-Cl, 3-Cl, 3-CH3, 4-SO2CH3, 4-Br and a positive contribution of 4-OCH3, 4-CH3 substituents at the R2 position. At the R3 position a negative contribution of F, Br and a positive contribution of Cl, CH3 is encountered. In the light of our preliminary investigation that electron donating groups at the para position of R2 are conducive for COX-2 inhibitory activity from the Fujita-Ban model, we attempted to correlate the COX-2 inhibitory activity with quantum chemical descriptors of semi-empirical AM1 optimized geometries of the title compounds. Correlation analysis showed the molecular electronic descriptor, MOPAC total energy as crucial in governing COX-2 inhibitory activity of all the reported 41 compounds.

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 analysis of a series of 2,3-diaryl benzopyran analogues as novel selective cyclooxygenase-2 inhibitors.

A series of recently synthesized 2,3-diaryl benzopyrans reported as novel selective cycloxygenase-2 inhibitors was subjected to quantitative structure-activity relationship (QSAR) analysis. Our attempt in correlating the derived physicochemical properties with the COX-2 inhibitory activity resulted in some statistically significant QSAR models with good predictive ability. The QSAR results and the probable pharmacophore features investigated through our study explored some interesting findings for the design of potent new class of selective COX-2 inhibitors.