David Montero Pereira

A computer-based approach to the rational discovery of new trichomonacidal drugs by atom-type linear indices

Computational approaches are developed to design or rationally select, from structural databases, new lead trichomonacidal compounds. First, a data set of 111 compounds was split (design) into training and predicting series using hierarchical and partitional cluster analyses. Later, two discriminant functions were derived with the use of non-stochastic and stochastic atom-type linear indices. The obtained LDA (linear discrimination analysis)-based QSAR (quantitative structure-activity relationship) models, using non-stochastic and stochastic descriptors were able to classify correctly 95.56% (90.48%) and 91.11% (85.71%) of the compounds in training (test) sets, respectively. The result of predictions on the 10% full-out cross-validation test also evidenced the quality (robustness, stability and predictive power) of the obtained models. These models were orthogonalized using the Randic orthogonalization procedure. Afterwards, a simulation experiment of virtual screening was conducted to test the possibilities of the classification models developed here in detecting antitrichomonal chemicals of diverse chemical structures. In this sense, the 100.00% and 77.77% of the screened compounds were detected by the LDA-based QSAR models (Eq. 13 and Eq. 14, correspondingly) as trichomonacidal. Finally, new lead trichomonacidals were discovered by prediction of their antirichomonal activity with obtained models. The most of tested chemicals exhibit the predicted antitrichomonal effect in the performed ligand-based virtual screening, yielding an accuracy of the 90.48% (19/21). These results support a role for TOMOCOMD-CARDD descriptors in the biosilico discovery of new compounds.

Synthesis and antibacterial activity of novel 4-aryl-[1,2,3]-triazole containing macrolides.

Two series of novel triazole containing 14-member macrolides having either a cladinose or a 3-pyridyl acetate group at the 3-position of the macrolide ring were synthesized. The in vitro antibacterial activities against S. aureus, S. pneumoniae, S. pyogenes and E. faecalis were determined. Macrolide 7a and the fluoroketolide 1 (CEM-101) were evaluated in vivo in murine systemic infection models. All of the macrolide analogs were less active in vitro and in vivo than the fluoroketolide 1 (CEM-101).

Efforts to Support the Development of Fusidic Acid in the United States

Fusidic acid (FA), though used widely throughout the world for decades, has never been approved in the United States. There is now a great need for an oral methicillin-resistant Staphylococcus aureus (MRSA) antibiotic with a long track record of safety. Cempra Pharmaceuticals successfully encouraged passage of a congressional amendment to allow for Hatch-Waxman market exclusivity when this antibiotic is approved in the United States. A new dosing regimen has been patented, allowing FA to be used as monotherapy, and decreased resistance selectivity has been shown. With almost no resistance to FA in the United States, the time is right for introduction into this market.

New Antitrichomonal Drug-like Chemicals Selected by Bond (Edge)-Based TOMOCOMD-CARDD Descriptors

Bond-based quadratic indices, new TOMOCOMD-CARDD molecular descriptors, and linear discriminant analysis (LDA) were used to discover novel lead trichomonacidals. The obtained LDA-based quantitative structure-activity relationships (QSAR) models, using nonstochastic and stochastic indices, were able to classify correctly 87.91% (87.50%) and 89.01% (84.38%) of the chemicals in training (test) sets, respectively. They showed large Matthews correlation coefficients of 0.75 (0.71) and 0.78 (0.65) for the training (test) sets, correspondingly. Later, both models were applied to the virtual screening of 21 chemicals to find new lead antitrichomonal agents. Predictions agreed with experimental results to a great extent because a correct classification for both models of 95.24% (20 of 21) of the chemicals was obtained. Of the 21 compounds that were screened and synthesized, 2 molecules (chemicals G-1, UC-245) showed high to moderate cytocidal activity at the concentration of 10 μg/ml, another 2 compounds (G-0 and CRIS-148) showed high cytocidal activity only at the concentration of 100 μg/ml, and the remaining chemicals (from CRIS-105 to CRIS-153, except CRIS-148) were inactive at these assayed concentrations. Finally, the best candidate, G-1 (cytocidal activity of 100% at 10 μg/ml) was in vivo assayed in ovariectomized Wistar rats achieving promising results as a trichomonacidal drug-like compound. (Journal of Biomolecular Screening 2008:785-794).

Nature nurtures the design of new semi-synthetic macrolide antibiotics

Erythromycin and its analogs are used to treat respiratory tract and other infections. The broad use of these antibiotics during the last 5 decades has led to resistance that can range from 20% to over 70% in certain parts of the world. Efforts to find macrolides that were active against macrolide-resistant strains led to the development of erythromycin analogs with alkyl-aryl side chains that mimicked the sugar side chain of 16-membered macrolides, such as tylosin. Further modifications were made to improve the potency of these molecules by removal of the cladinose sugar to obtain a smaller molecule, a modification that was learned from an older macrolide, pikromycin. A keto group was introduced after removal of the cladinose sugar to make the new ketolide subclass. Only one ketolide, telithromycin, received marketing authorization but because of severe adverse events, it is no longer widely used. Failure to identify the structure-relationship responsible for this clinical toxicity led to discontinuation of many ketolides that were in development. One that did complete clinical development, cethromycin, did not meet clinical efficacy criteria and therefore did not receive marketing approval. Work on developing new macrolides was re-initiated after showing that inhibition of nicotinic acetylcholine receptors by the imidazolyl-pyridine moiety on the side chain of telithromycin was likely responsible for the severe adverse events. Solithromycin is a fourth-generation macrolide that has a fluorine at the 2-position, and an alkyl-aryl side chain that is different from telithromycin. Solithromycin interacts at three sites on the bacterial ribosome, has activity against strains resistant to older macrolides (including telithromycin), and is mostly bactericidal. Pharmaceutical scientists involved in the development of macrolide antibiotics have learned from the teachings of Professor Satoshi Omura and progress in this field was not possible without his endeavors.