Computational POM evaluation of experimental in vitro Trypanosoma cruzi and Mycobacterium tuberculosis inhibition of heterocyclic-2-carboxylic acid (3-cyano-1,4-di-noxidequinoxalin-2-yl)amide derivatives

A computation model has been developed for the rational design of bioactive pharmacophore sites as anti-Mycobacterium tuberculosis and anti-Trypanosoma cruzi (TC) candidates. The 40 compounds 1–40 analyzed have been previously screened for their antitubercular and antitrypanosomal activity. The highest anti-TC activity is obtained for compounds 8 and 18 which exhibited low IC₅₀ values (9.2 and 10.8 μM), almost equal to clinical drug, nifurtimox (7.7 μM; 100 % Inhib.). This could be attributed to the existence of two synergic (O ^δ?–N ^δ?) and (O ^δ?–O ^δ?) antitrypanosomal pharmacophore sites. In contrast to compounds 8 and 18 which contain electro-attractor groups (R¹, R² = F), analog compounds 1 and 13 with electro-donor or only hydrogen (R¹, R² = CH₃, H) show best antibacterial activity (MIC = 0.977 and 1.190 μg/mL) very close to antitubercular activity of Rifampicin (MIC = 0.125 μg/mL). This could be attributed to the existence of (O ^δ?–NH ^δ+) antibacterial pharmacophore site.     

Non-invasive ventilation after extubation in patients with chronic obstructive airways disease: a randomised controlled trial

Non-invasive positive pressure ventilation (NPPV) is a well established therapy for acute respiratory failure in patients with chronic obstructive pulmonary disease, however its role in post-extubation period is uncertain. The objective of this study was to find the effect of NPPV on rate of re-intubation, intensive care unit and hospital stay, and physiological parameters in severe chronic obstructive pulmonary disease patients after planned extubation. Forty patients with severe chronic obstructive pulmonary disease were randomised immediately after planned extubation to receive NPPV (n=20) or conventional therapy (n=20). NPPV was delivered with mean levels of inspiratory positive-airway pressure of 12.10 +/- 1.37 cmH2O and expiratory positive-airway pressure of 6.50 +/- 1.00 cmH2O for a mean period of 34.75 +/- 10 hours for 7 to 11 hours/day. Patients in conventional therapy group received usual treatment. Reintubation rate among NPPV (15%) and conventional (25%) were similar (P=0.44). The duration of intensive care unit stay after extubation (2.05 +/- 2.15 vs 1.55 +/- 0.82 days, P=0.34) and hospital stay (16.10 +/- 6.29 vs 18.25 +/- 7.91 days, P=0.34) in both groups were comparable. Given the load of chronic obstructive pulmonary disease patients and wide availability of NPPV it is safe to recommend its use in these patients soon after extubation, although clear benefit is not documented in this study.     

Synthesis, characterization, and urease inhibition of 5-substituted-8-methyl-2H-pyrido[1,2-a]pyrimidine-2,4(3H)-diones

Abstract  

5-Substituted-8-methyl-2H-pyrido[1,2-a]pyrimidine-2,4(3H)-dione and its anilines, amino pyridines and hydrazides derivatives were prepared in a good to excellent yields. In the first step 8-methyl-2H-pyrido[1,2-a]pyrimidine-2,4(3H)-dione (1) was prepared by reacting 4-methyl-2-aminopyridine, with diethylmalonate. Compounds substituted pyrido[1,2-a]pyrimidine-2,4(3H)-diones (PPMDO) (2)–(17) were prepared by condensing 8-methyl-2H-pyrido[1,2-a]pyrimidine-2,4(3H)-dione in the presence of triethylorthoformte (TEF) and dimethylformamide (DMF), with respective amino components viz. 2-aminoacetophenone, 3-aminoacetophenone, 4-aminoacetophenone, 2,4,6-trimethylaniline, 2-fluoroaniline, 3-fluoroaniline, 4-fluoroaniline, 2-aminothiophenol, 2-amino-4-methylpyridine, 2-amino-5-methylpyridine, 2-amino-5-nitropyridine, Benzoic hydrazide, 4-nitrobenzoic hydrazide, 4-bromobenzoic hydrazide, 4-chlorobenzoic hydrazide and 4-hydroxybenzoic hydrazide, respectively. The chemical structures of all the compounds were elucidated by IR, ¹H-NMR, ¹³C-NMR and elemental analysis data. The synthesized compounds were screened for their in vitro urease inhibition activity, by the phenol hypochlorite method. These compounds were found to exhibit either no or low to moderate or significant activity. The compounds (9) and (14) showed comparatively much higher activity. However, the compound (9) was found to be the most active one.     

QSAR and CoMFA studies of biphenyl analogs of the anti-tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo [2,1-b][1,3]oxazine (PA-824)

With the purpose of designing new chemical entities with enhanced inhibitory potencies against Mycobacterium tuberculosis, the 3D-QSAR CoMFA study carried out on biphenyl analogs of the tuberculosis drug, (6S)-2-nitro-6-{[4-trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824), is presented here. The developed model showed a good correlative and predictive ability. The final QSAR models as well as the information gathered from 3D contour maps should be useful for the design of novel PA-824 analogs having improved anti-TB activity.     

Synthesis, biopharmaceutical characterization, and antimicrobial study of novel azo dyes of 7-hydroxy-4-methylcoumarin

Herein, we report the synthesis and biopharmaceutical characterization of coumarin based azo compounds. The novel coumarin based azo compounds were obtained by the coupling of bis-coumarin (2Z,2′Z)-2,2′-[ethane-1,2-diylbis(azan-1-yl-1-ylidene)]bis(4-methylchroman-7-ol) with diazotized aromatic amines. The compounds were fully characterized using spectroscopic analytical method and tested for their antibacterial and antifungal activity. A correlation of structure and activities relationship of these compounds with respect to molecular modeling, Lipinski rule of five, drug-likeness, toxicity profiles, and other physico-chemical properties of drugs are described and verified experimentally.