Showing papers by "Pallu Reddanna published in 2006"

Functional correlation of cyclooxygenases -1, 2 and 3 from amino acid sequences and three dimensional model structures

Abstract: COX-1, COX-2 and COX-3, three isoforms of cyclooxygenase are differentially expressed. We have analyzed the sequences of these cyclooxygenases and built the three dimensional model structures for human COX-1 COX-2 and canine COX-3 to characterize the function of cyclooxygenase isozymes based on the sequence and structure information. Sequence analysis reveals that COX-3 shares 90% homology with COX-1 and 60% with COX-2. The LOX-1 model has been compared with those of COX-2 and COX-3 and the active site regions have been analyzed. The major differences in the active sites of COX-1 and COX-2 are: lie 523 in COX-1 is replaced by Val in COX-2, apart from a few mutations at the mouth of the active site. No such differences in the active sites are seen between COX-1 and COX-3 structures and the amino acid residues that differ between COX-1 and COX-3 lie only on the surface of the protein. Therefore, it is hard to explain the specificity of acetaminophen towards COX-3. Further, the intron 1 of canine COX-1 gene that is retained in COX-3 mRNA transcript codes for a poly proline region that could be responsible for intermolecular interactions.

Synthesis of (2-(3-oxo-3,4-dihydro-2H-benzo(1,4)oxazin-6- carbonyl)-1H-indol- 3-yl)acetic acids as potential COX-2 inhibitors

Abstract: The synthesis of potential COX-2 inhibitors by means of internal Michael addition of ortho toluenesulfonylaminophenyl acrylic acid methyl esters 5a-d with 6-(chloroacetyl)-2H-1,4-bezoxazin-4H-ones 6a-c followed by hydrolysis resulting in the formation of [2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-carbonyl)-1H-indol-3-yl]acetic acids 1a-k are reported.

Synthesis of methyl-5-[2-arylamino-4-(3-oxo-1,4-benzoxazin-6-yl)thiazole acetates and 7 H -[3-aryl-6-(3-oxo-1,4-benzoxazin-6-yl)- s -triazolo[3,4- b ][1,3,4]thiadiazin-7-yl]acetates as possible COX-2-inhibitors

Abstract: A series of methyl 5-[2-arylamino-4-(3-oxo-[1,4]benzoxazin-6-yl)thiazoleacetates 5a-h and 7H-[3-aryl-6-(3-oxo-[1,4]-benzox-azin-6-yl)-s-triazolo[3,4-b][1,3,4]thiadiazin-7-yl]acetates 6a-e have been synthesized and tested for their COX-2 inhibitor activity.

A comparison of computer aided drug design methods for calculating relative binding affinities of COX-2 inhibitors

Abstract: Computational assessment of the binding affinity of enzyme inhibitors prior to synthesis is an important component of computer-aided drug design paradigms. The free energy perturbation methodology is the most accurate means of estimating relative binding affinities between two inhibitors. However, due to its complexity and computation-intensive nature, practical applications are restricted to analysis of structurally-related inhibitors. Accordingly, there is a need for methods that enable rapid assessment of a large number of structurally-unrelated molecules in a suitably accurate manner. In this article, the free energy perturbation method is compared with molecular mechanics methods to assess the advantages of each in the estimation of relative binding affinities of COX-2 inhibitors. Qualitative predictions of relative binding free energies of COX-2 inhibitors using molecular mechanics methods are discussed and compared with the corresponding free energy perturbation results. The results indicate that the molecular mechanics based methods are useful in the qualitative assessment, while the free energy methods are useful in the quantitative assessment of relative binding affinities of enzyme inhibitors.

Synthesis of 4 H -imidazo[2,1- c ][1,4]benzo­xazin-4-yl acetic acids and esters as possible COX-2 inhibitors

Abstract: A series of 4H-imidazol[2,1-c][1,4]benzoxazin-4-yl acetic acids and esters (7 and 8) have been synthesized from methyl a-(3,4-dihydro-3-oxo-2H-1,4-benzoxazin-yl)acetates 5 and their COX-2 inhibition activities are evaluated.

Synthesis of 4H‐Imidazo[2,1‐c][1,4]benzoxazin‐4‐yl Acetic Acids and Esters as Possible COX‐2 Inhibitors.

Abstract: Although, non-steroidal anti-inflammatory drugs (NSAIDS), have been used in the treatment of various inflammatory diseases, their usage is limited by the side effects produced by them, thereby necessitating the need for searching new molecular entities. A number of aryl and heteroaryl substituted acetic acids such as Diclofenac 1, Lumiracoxib 2, Lonazolac 3, Etodolac 4 have been commercialized as NSAIDS. Several imidazoazines have been reported to possess significant pharmacological activities. Otsuka et al. isolated a number of 1,4-benzoxazinone derivatives from the roots of Coix lachryma – jobi which have been used in treatment of neuralgia, rheumatism and inflammatory diseases. Furthermore, recently several 2-substituted benzoxazinones have been reported as smooth muscle relaxants, anticoagulant and antibacterial agents. In addition, a new series of benzoxazinones were reported useful in the treatment of type 2 diabetes which does not contain thiazolidenedione. In view of these observations and in continuation of our work on new benzoxazines, it was considered of interest to synthesize some new imidazobenzoxazinyl acetic acids and evaluate their COX-2 inhibitor activity. Methyl α-(3,4-dihydro-3-oxo-2H-1,4-benzoxazin2-yl)acetates 5 required as starting materials in the present work, were prepared by the reaction of substituted 2-aminophenols with maleic anhydride in refluxing methanol in the presence of triethylamine according to the procedure described earlier. Reaction of 5 with various ω-haloacetophenones in refluxing acetone in the presence of anhydrous potassium carbonate and tetrabutylammonium bromide as phase transfer catalyst gave the N-alkylated benzoxazinones 6 in excellent yields. H NMR spectra of 6 exhibited characteristic signals around δ 3.76-3.78 (CO2CH3), 2.98-3.06 (2 × dd, CH2CO2CH3), 5.0-5.03 (m, OCH) and 5.31-5.34(ABq, -NCH2-CO) apart from other aromatic protons. IR spectra of 6 exhibited characteristic ester, amide and ketone carbonyl in the region 1735, 1690 cm. Cyclocondensation of 6 in acetic acid in presence of ammonium acetate gave the targeted imidazobenzoxazinyl acetates 7 in good yields (IR 1737 cm). Hydrolysis of representative 7 in aqueous methanolic NaOH furnished the corresponding acetic acids 8 as colourless crystalline solids (Scheme I). Structures of compounds 7 were established based on their H NMR, IR, mass spectra and correct elemental analyses. In the H NMR spectra of 7, the ester group appeared as a singlet at δ 3.76, the methylene protons of ester group appeared as two sets of double doublets at δ 3.06 and 3.42 whereas OCH proton appeared as a double doublet at δ 5.74 apart from C1-imidazoproton (δ 7.4-7.5, singlet) and other aromatic protons.