Structure-Activity Relationships on Purine and 2,3-Dihydropurine Derivatives as Antitubercular Agents: A Data Mining Approach

Centro Interdipartimentale di Farmacologia Clinica e Terapia Sperimentale, University of Pisa, Pisa, Italy.
Chemical Biology &amp Drug Design (Impact Factor: 2.49). 07/2011; 78(4):718-24. DOI: 10.1111/j.1747-0285.2011.01181.x
Source: PubMed


Nowadays, many people still fall victim to tuberculosis, the disease that has a worldwide spreading. Moreover, the problem of resistance to isoniazid and rifampin, the two most effective antitubercular drugs, is assuming an ever-growing importance. The need for new drugs active against Mycobacterium tuberculosis represents nowadays a quite relevant problem in medicinal chemistry. Several purine and 2,3-dihydropurine derivatives have recently emerged, showing considerable antitubercular properties. In this work, a quantitative structure-activity relationship (QSAR) model was developed, which is able to predict whether new purine and 2,3-dihydropurine derivatives belong to an 'Active' or 'Inactive' class against the above micro-organism. The obtained prediction model is based on a classification tree; it was built with a small number of descriptors, which allowed us to outline structural features important to predict antitubercular activity of such classes of compounds.

Download full-text


Available from: Alice Borghini, Oct 06, 2015
22 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Thio analogues of purine, pyridine, and pyrimidine were prepared based on the initial activity screening of several analogues of these heterocycles against Mycobacterium tuberculosis (Mtb). Certain 6-thio-substituted purine analogues described herein showed moderate to good inhibitory activity. In particular, two purine analogues 9-(ethylcarboxymethyl)-6-(decylthio)-9H-purine (20) and 9-(ethylcarboxymethyl)-6-(dodecylthio)-9H-purine (21) exhibited MIC values of 1.56 and 0.78 microg/mL respectively against the Mtb H(37)Rv strain. N(9)-Substitution apparently enhances the antimycobacterial activity in the purine series described herein.
    Journal of Medicinal Chemistry 02/2004; 47(1):273-6. DOI:10.1021/jm030389b · 5.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In response to the need for rapid, inexpensive, high-throughput assays for antimycobacterial drug screening, a microplate-based assay which uses Alamar blue reagent for determination of growth was evaluated. MICs of 30 antimicrobial agents against Mycobacterium tuberculosis H37Rv, M. tuberculosis H37Ra, and Mycobacterium avium were determined in the microplate Alamar blue assay (MABA) with both visual and fluorometric readings and compared to MICs determined in the BACTEC 460 system. For all three mycobacterial strains, there was < or = 1 dilution difference between MABA and BACTEC median MICs in four replicate experiments for 25 to 27 of the 30 antimicrobics. Significant differences between MABA and BACTEC MICs were observed with 0, 2, and 5 of 30 antimicrobial agents against H37Rv, H37Ra, and M. avium, respectively. Overall, MICs determined either visually or fluorometrically in MABA were highly correlated with those determined in the BACTEC 460 system, and visual MABA and fluorometric MABA MICs were highly correlated. MICs of rifampin, rifabutin, minocycline, and clarithromycin were consistently lower for H37Ra compared to H37Rv in all assays but were similar for most other drugs. M. tuberculosis H37Ra may be a suitable surrogate for the more virulent H37Rv strain in primary screening of compounds for antituberculosis activity. MABA is sensitive, rapid, inexpensive, and nonradiometric and offers the potential for screening, with or without analytical instrumentation, large numbers of antimicrobial compounds against slow-growing mycobacteria.
    Antimicrobial Agents and Chemotherapy 06/1997; 41(5):1004-9. · 4.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Azidolysis of epoxides followed by reduction of the intermediate azido alcohols constitutes a valuable synthetic tool for the construction of beta-amino alcohols, an important chemical functionality occurring in many biologically active compounds of natural origin. However, depending on conditions under which the azidolysis is carried out, two regioisomeric products can be formed, as a consequence of the nucleophilic attack on both the oxirane carbon atoms. In this work, predictive models for quantitative structure-reactivity relationships were developed by means of multiple linear regression, k-nearest neighbor, locally weighted regression, and Gaussian Process regression algorithms. The specific nature of the problem at hand required the creation of appropriate new descriptors, able to properly reflect the most relevant features of molecular moieties directly involved in the opening process. The models so obtained are able to predict the regioselectivity of the azidolysis of epoxides promoted by sodium azide, in the presence of lithium perchlorate, on the basis of steric hindrance, and charge distribution of the substituents directly attached to the oxirane ring.
    Journal of Computational Chemistry 11/2010; 31(14):2612-9. DOI:10.1002/jcc.21556 · 3.59 Impact Factor
Show more