Search of Chemical Scaffolds for Novel Antituberculosis Agents

A method to identify chemical scaffolds potentially active against Mycobacterium tuberculosis is presented. The molecular features of a set of structurally heterogeneous antituberculosis drugs were coded by means of structural invariants. Three techniques were used to obtain equations able to model the antituberculosis activity: linear discriminant analysis, multilinear regression, and shrinkage estimation–ridge regression. The model obtained was statistically validated through leave-n-out test, and an external set and was applied to a database for the search of new active agents. The selected compounds were assayed in vitro, and among those identified as active stand reserpine, N,N,N′,N′-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN), trifluoperazine, pentamidine, and 2-methyl-4,6-dinitro-phenol (DNOC). They show activity comparable to or superior to ethambutol, used in combination with other drugs for the prevention and treatment of Mycobacterium avium complex and drug-resistant tuberculosis.

[1]  R. García-Domenech,et al.  General topological patterns of known drugs. , 2001, Journal of molecular graphics & modelling.

[2]  J. Gálvez,et al.  New Analgesics Designed by Molecular Topology , 1996 .

[3]  Ramón García-Domenech,et al.  New agents active against Mycobacterium avium complex selected by molecular topology: a virtual screening method. , 2003, Journal of Antimicrobial Chemotherapy.

[4]  J. Ungwitayatorn,et al.  Quantitative structure-activity relationship (QSAR) study of polyhydroxyxanthones. , 1997, Pharmaceutica acta Helvetiae.

[5]  E Uriarte,et al.  Recent advances on the role of topological indices in drug discovery research. , 2001, Current medicinal chemistry.

[6]  D. Bonchev,et al.  Overall connectivity--a next generation molecular connectivity. , 2001, Journal of molecular graphics & modelling.

[7]  Ramon Carbó-Dorca,et al.  Similarity approach to QSAR. Application to antimycobacterial benzoxazines. , 2004, International journal of pharmaceutics.

[8]  Ramón García-Domenech,et al.  Molecular connectivity to find β-blockers with low toxicity , 1997 .

[9]  A Tropsha,et al.  Identification of the descriptor pharmacophores using variable selection QSAR: applications to database mining. , 2001, Current pharmaceutical design.

[10]  J. Gálvez,et al.  Molecular topology: a useful tool for the search of new antibacterials. , 2000, Bioorganic & medicinal chemistry letters.

[11]  R. R. Hocking.  Criteria for Selection of a Subset Regression: Which One Should Be Used? , 1972 .

[12]  D. Mitchison,et al.  Early Bactericidal Activity of Paromomycin (Aminosidine) in Patients with Smear-Positive Pulmonary Tuberculosis , 2000, Antimicrobial Agents and Chemotherapy.

[13]  A. E. Hoerl,et al.  Ridge regression: biased estimation for nonorthogonal problems , 2000 .

[14]  M. Iseman,et al.  The increasing prevalence of resistance to antituberculosis chemotherapeutic agents: implications for global tuberculosis control. , 1992, Current clinical topics in infectious diseases.

[15]  E. Besalú,et al.  Virtual generation of agents against Mycobacterium tuberculosis. A QSAR study , 2004, Molecular Diversity.

[16]  J. Maddry,et al.  Antimycobacterial activity of 1-deaza-7,8-dihydropteridine derivatives against Mycobacterium tuberculosis and Mycobacterium avium complex in vitro. , 2001, The Journal of antimicrobial chemotherapy.

[17]  Feldman Wh.  Chemotherapy of Tuberculosis , 1946 .

[18]  J. Rugutt,et al.  Relationships between Molecular Properties and Antimycobacterial Activities of Steroids , 2002, Natural product letters (Print).

[19]  W. Steinmetz.  A CoMFA Model of Steric and Electronic Effects of Phosphorus Ligands , 1996 .

[20]  T. Shinnick,et al.  Mycobacterial taxonomy , 2005, European Journal of Clinical Microbiology and Infectious Diseases.

[21]  L B Kier,et al.  General definition of valence delta-values for molecular connectivity. , 1983, Journal of pharmaceutical sciences.

[22]  A. García-García,et al.  QSAR by molecular topology of 2,4-dihydroxythiobenzanilides-·A virtual screening approach to optimize the antifungal activity , 2002 .

[23]  S. Basak,et al.  Usefulness of graphical invariants in quantitative structure–activity correlations of tuberculostatic drugs of the isonicotinic acid hydrazide type , 2004, Journal of molecular modeling.

[24]  Emili Besalú,et al.  Fast Computation of Cross-Validated Properties in Full Linear Leave-Many-Out Procedures , 2001 .

[25]  D. Gadre,et al.  In vitro susceptibility testing of Mycobacterium tuberculosis strains to trifluoperazine. , 1999, Journal of chemotherapy.

[26]  Jouko Yliruusi,et al.  Prediction of physicochemical properties based on neural network modelling. , 2003, Advanced drug delivery reviews.

[27]  W. Doucette.  Quantitative structure‐activity relationships for predicting soil‐sediment sorption coefficients for organic chemicals , 2003, Environmental toxicology and chemistry.

[28]  J P Doucet,et al.  Application of topological descriptors in QSAR and drug design: history and new trends. , 2002, Current drug targets. Infectious disorders.

[29]  J. Gálvez.  Use of molecular topology in the selection of new cytostatic drugs , 2000 .

[30]  S. Agatonovic-Kustrin,et al.  Molecular descriptors that influence the amount of drugs transfer into human breast milk. , 2002, Journal of pharmaceutical and biomedical analysis.

[31]  Martha Windholz.  The Merck index: an encyclopedia of chemicals, drugs, and biologicals , 1983 .

[32]  K. Schaper,et al.  Substituted Xanthones as Antimycobacterial Agents , 1999 .

[33]  J. Gálvez,et al.  New bronchodilators selected by molecular topology. , 1998, Bioorganic & medicinal chemistry letters.

[34]  L Pastor,et al.  New antifungals selected by molecular topology. , 1998, Bioorganic & medicinal chemistry letters.

[35]  Anton J Hopfinger,et al.  Rational design of new antituberculosis agents: receptor-independent four-dimensional quantitative structure-activity relationship analysis of a set of isoniazid derivatives. , 2004, Journal of medicinal chemistry.

[36]  D. Sureja,et al.  Synthesis and QSAR studies of 4-substituted phenyl-2,6-dimethyl-3, 5-bis-N-(substituted phenyl)carbamoyl-1,4-dihydropyridines as potential antitubercular agents. , 2001, Bioorganic & medicinal chemistry.

[37]  Jorge Gálvez,et al.  Charge Indexes. New Topological Descriptors , 1994, J. Chem. Inf. Comput. Sci..

[38]  H. Wiener.  Structural determination of paraffin boiling points. , 1947, Journal of the American Chemical Society.

[39]  R. García-Domenech,et al.  Virtual combinatorial syntheses and computational screening of new potential anti-herpes compounds. , 1999, Journal of medicinal chemistry.

[40]  Rafael Gozalbes,et al.  Prediction of Quinolone Activity against Mycobacterium avium by Molecular Topology and Virtual Computational Screening , 2000, Antimicrobial Agents and Chemotherapy.

[41]  E. Bouza,et al.  In Vitro Activities of Linezolid against Clinical Isolates of Mycobacterium tuberculosis That Are Susceptible or Resistant to First-Line Antituberculous Drugs , 2003, Antimicrobial Agents and Chemotherapy.

[42]  M. Randic,et al.  The connectivity index 25 years after. , 2001, Journal of molecular graphics & modelling.

[43]  J. Gálvez,et al.  Pharmacological distribution diagrams: a tool for de novo drug design. , 1996, Journal of molecular graphics.

[44]  G. Marshall,et al.  Antimycobacterial pyrroles: synthesis, anti-Mycobacterium tuberculosis activity and QSAR studies. , 2000, Bioorganic & medicinal chemistry.

[45]  L B Kier,et al.  Molecular connectivity V: connectivity series concept applied to density. , 1976, Journal of pharmaceutical sciences.

[46]  R. Kaliszan,et al.  Imidazo[4,5‐b]pyridine Derivatives of Potential Tuberculostatic Activity. Part 1: Synthesis and Quantitative Structure‐Activity Relationships , 1991, Archiv der Pharmazie.

[47]  Jesús Vicente de Julián-Ortiz,et al.  Topological Approach to Drug Design , 1995, J. Chem. Inf. Comput. Sci..

[48]  M. J. Duart,et al.  Search of a Topological Pattern to Evaluate Toxicity of Heterogeneous Compounds , 2001, SAR and QSAR in environmental research.

[49]  E. Ferreira,et al.  Potential tuberculostatic agents. Topliss application on benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazide series. , 2002, Bioorganic & medicinal chemistry.

[50]  Ramón García-Domenech,et al.  Search for New Antihistaminic Compounds by Molecular Connectivity , 1999 .

[51]  W. P. Dixon,et al.  BMPD statistical software manual , 1988 .

[52]  Prediction of chromatographic properties of organophosphorus Insecticides by molecular connectivity , 2000 .

[53]  Braun.  [Chemotherapy of tuberculosis of the skin]. , 1950, Archiv für Dermatologie und Syphilis.

[54]  Ramón García-Domenech,et al.  Designing sedative/hypnotic compounds from a novel substructural graph-theoretical approach , 1998, Journal of computer-aided molecular design.

[55]  E Estrada,et al.  Novel local (fragment-based) topological molecular descriptors for QSpr/QSAR and molecular design. , 2001, Journal of molecular graphics & modelling.

[56]  George M. Furnival,et al.  Regressions by leaps and bounds , 2000 .