Current Issue : October - December Volume : 2012 Issue Number : 4 Articles : 9 Articles
The development of new therapies to treat tuberculosis effectively is currently an intensive area of research, as there is development of total resistance to present marketed drugs available for tuberculosis. To achieve this objective, quantitative structure activity relationship (QSAR) study was carried out on a series of 1,4- dihydropyridine derivatives reported as inhA inhibitors as it provides the rationale for the changes in the pharmacophore to have more potent and less toxic analogues. In this article, we report 2D and 3D QSAR studies for the set of 20 molecules. Statistically significant models were generated, and the most robust model for 2D quantitative structure activity relationship was obtained using Multiple linear regression (MLR), Principle component regression (PCR) and Partial least square regression (PLSR) technique. The 3D QSAR model was developed by Simulated Annealing kohonen Nearest Neighbor Molecular Field Analysis (SA kNN MFA). By performing 2D QSAR, we found that multiple linear regression method showed best statistical result when compared with other methods. The model has shown correlation coefficient (r2), cross validation (q2) and external validation (pred_r2) values of 0.8052, 0.7096 and 0.7567 respectively. The 3D QSAR models were generated to study the effect of steric, electrostatic and hydrophobic descriptors on antitubercular activity. The generated model with good external and internal predectivity for the training and test set that shown cross validation (q2) and external validation (pred_r2) values of 0.7353 and 0.8043, respectively. The electronic, steric and hydrophobic descriptors generated at the points E_796, S_755 and H_944 play an important role in the design of new molecule. Thus 2D and 3D QSAR studies were found to reliable clues for further optimization of 1,4-dihydropyridine pharmacophore as effective antitubercular agents....
The major concerns for current TB treatment are its latency, co-infection with HIV, poor patient compliance, and drug resistance issues. Therefore, it is an imperative need to develop novel anti-tubercular drugs that can be equally effective against Mycobacterium tuberculosis and drug resistant strains, and shorten the duration of therapy. The antitubercular activity of pyridine containing compounds is being investigated from early days. We have optimized pharmacophoric requirements with 2D & 3D QSAR studies using V Life Molecular Design Suite software. Statistical methods like multiple linear regression (MLR), principle component regression (PCR), and partial least square regression (PLSR) technique were used as model building methods. In 2D QSAR, we found that partial least square regression method showed best statistical result when compared with other methods. The 3D QSAR model was developed by kohonen Nearest Neighbour Molecular Field Analysis (kNN MFA) method using simulated annealing as a variable selection method. Generation of rigorously validated QSAR model is important to ensure that the model have acceptable predictive power. With the help of QSAR results optimization of pharmacophore was carried out to identify key structural fragments required around pharmacophore for antitubercular activity. Results of QSAR studies yielded good, reliable models having scientifically acceptable, predictive ability i.e. the satisfactory statistical values of r2 greater than 0.7 and q2 greater than 0.5 etc....
The small and simple indole nucleus and its derivatives possess various diverse biological properties. It possesses good antimicrobial activity. Literature survey reveals that indole is a heterocycle on which substitution with another heterocycle or bulky group shows increased activity. In such a way it acts as a promising lead for potent antimicrobial activity....
Drug discovery requirement is to have a highly potent hit that has to be optimized to remove undesirable characteristics such as poor oral bioavailablity, metabolic stability or toxicity. In medicinal chemistry, isosterism, bioisosterism and scaffold hopping are research tools that have been successfully applied for designing new pharmacotherapeutically attractive substances. Isostere are group of atoms that impart similar physical or chemical properties to a molecule while substituents imparting similar biological properties on a compound are termed bioisostere. Bioisosteric replacement allows a medicinal chemist to modulate the physicochemical properties, selectivity, toxicity and pK characteristics of a small molecule while maintaining or improving its primary binding activity. Bioisosterism may alter the metabolism of the lead, and acquire novel intellectual property. The scaffold hopping techniques assist to identify structurally novel compounds by modifying the central core structure of the molecule and yet binding to the same molecular target. This review covers the developments in the fields of isosterism, bioisosterism and scaffold hopping in drug discovery. Various drugs developed or being developed using these strategies, and various software employed in the identification of isosteresc/bioisosters scaffold hopping are included. Moreover, combined bioisosteric replacement in different molecules has bright future in drug discovery. Experts are of the opinion that the knowledge generated in this direction has the potential towards accelerated development of better and effective drugs that could potentially treat the disorder they are researching, particularly to control autoimmune disorders and cardiovascular disorders where limited knowledge is available at present....
The re-emergence of XDR & MDR tuberculosis have claimed human life potentially. We here note down details of designing and synthesis of several pyrimido-thiazolyl triazole derivatives and their evaluation against 25 different clinical isolates. “Hit” is identified through this series of compounds which has shown promising activity compared with Isoniazid. The candidate is under further trials for identifying the toxophore and to avoid untoward effects....
A simple, efficient procedure for the one-pot Biginelli condensation reaction of aldehydes, β-ketoesters and urea or thiourea without using any catalyst or solvent is described. Compared to the classical Biginelli reaction conditions, the present method has the advantages of good yields, short reaction times and experimental simplicity. The structure of these compounds was confirmed by analytical M.P. IR, 1HNMR, 13C-NMR, Mass spectral data. The above compounds were evaluated for their antioxidant activity by reducing power and DPPH Free Radical Scavenging Assay. In reducing power the percentage of inhibition of 3, 4-dihydropyrimidin-2(1H)-one derivatives S1, S3, and S4 were found 84.05%,85.50%, 91.30% at 150 μg/mL and for S2 were found to be 94.20% at 125 μg/mL, Similarly in DPPH the percentage of inhibition of of 3, 4-dihydropyrimidin- 2(1H)-one derivatives S1 and S2 were found 77.23% , 82.73% at 125 μg/mL and S3 and S4 were found 84.27%, 63.29% at 150 μg/mL respectively....
QSAR study has been performed on series quinoxaline derivatives for their antitubercular activity against Mycobacterium tuberculosis H37Rv. Ten QSAR models have been developed between activity and molecular descriptors and were obtained as multiple linear regression (MLR) equations. The statistical measures such as r, r2, q2, chance, Spress, SDEP, FIT and F values obtained for training set were in acceptable range and hence the relationship was used for test set. The predictive ability for the model equation 1 is satisfactory (q2 = 0.7086) and revealed positive contribution of Henry’s law constant (HLC) and negative contribution of both bend energy (Eb) and Dipolemoment (D4). The best optimized model is BA = [-0.77707(± 0.116356)] +HLC [0.0207407(± 0.0116089)] + Eb [-0.00432891(± 0.00110419)] +D4 [-0.0157226(± 0.0126022)]....
A series of novel 3,5-dichloro-4-((3-aryl isoxazol-5-yl)methoxy)phenyl) aryl methanones (9a-f), were synthesized by condensing 3-aryl-5-methanesulfonyl methylisoxazoles (8a-c) with aryl(3,5-dichloro-4-hydroxyphenyl) methanones (4a-b) using TBAB and K2CO3. The chemical structure of the newly synthesised compounds was characterized by analytical and spectral (IR, 1H NMR, and LC-MS) methods. The title compounds were screened for qualitative (zone of inhibition) and quantitative antimicrobial activity (MIC) by agar well and microbroth dilution technique, repectively. Among the synthesized compounds in the series, the compounds 9b and 9e were found to exhibit significant antibacterial activity at lower concentration, against Gram positive bacteria such as Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis, and Bacillus cereus and Gram negative bacteria such as E.coli, Pseudomonas aeruginosa, Salmonella typhi, and Klebsiella pneumoniae. The compounds 9b and 9e were also exhibited potent activity against filamentous fungi such as Aspergillus niger and yeast Candida albicans. The other compounds displayed moderate antimicrobial activity when compared to the standard positive controls gentamicin and nystatin....
The major drawback of current treatment of infectious diseases are challenging due to resistance to antimicrobial agents and their side effects. Benzimidazole and (β-lactam) Azetidinone are the heterocyclic compounds with considerable therapeutic and pharmacological properties. In this view, the series of Azetidinone encompassing Benzimidazole with different substitution were synthesized and evaluated for antibacterial and antitubercular activities. Series of 6 compounds having Benzimidazole and Azetidinone derivatives have been synthesized. These compounds were evaluated for antibacterial and antitubercular activities. In-vitro antibacterial activity of synthesized compound was tested against Gram positive and Gram negative microorganisms (Staphylococcus aureus MTCC 96, Bacillus subtilis MTCC 121 and Escherichia coli MTCC 521) respectively by filter paper disk method and the antitubercular activity against INH resistant Mycobacterium tuberculosis H37Rv, using the L.J. slope method. All the compounds were characterized by UV, IR, Mass and NMR. All Compounds possess a molecular ion M+2 peak due to presence of chlorine. In the 1H NMR δ value obtained in the range of 7.2 to 8.2 signifies the presence of aromatic ring and δ value at about 3.0 to 4.0 corresponds to the presence of methylene protons. In antibacterial screening all compounds found to have more activity against gram negative bacteria E.coli. Compounds 6a, 6d and 6e found to have better antibacterial activity against gram negative bacteria E.coli. Compound 6f have better antibacterial activity against gram+ve bacteria S.aureus and B.subtilis as compared to other synthesized compounds. Among the ring substituted azetidinone derivatives (6a to 6f) were tested for their antitubercular activity in vitro against INH resistant Mycobacterium tuberculosis H37Rv, using the L.J. slope method. Compounds 6a and 6e were found to be most potent among the series having MIC 100 μg/ml, others synthesized compounds were found to be active (having MIC 250μg/ml: 6b, 500μg/ml: 6d & 6f, 750 μg/ml: 6c). None of the compound was found to be equipotent with standard isoniazid....
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