Analysis of ergonomics problems contact-centers

The analysis of the ergonomic problems of the contact center. It allocates main factors of influence on man- operator

Desmethyl Macrolides: Synthesis and Evaluation of 4,8,10-Tridesmethyl Cethromycin

Antibiotic-resistant bacteria are emerging at an alarming rate in both hospital and community settings. Motivated by this issue, we have prepared desmethyl (i.e., replacing methyl groups with hydrogens) analogues of third-generation macrolide drugs telithromycin (TEL, <b>2</b>) and cethromycin (CET, <b>6</b>), both of which are semisynthetic derivatives of flagship macrolide antibiotic erythromycin (<b>1</b>). Herein, we report the total synthesis, molecular modeling, and biological evaluation of 4,8,10-tridesmethyl cethromycin (<b>7</b>). In MIC assays, CET analogue <b>7</b> was found to be equipotent with TEL (<b>2</b>) against a wild-type <i>E. coli</i> strain, more potent than previously disclosed desmethyl TEL congeners <b>3</b>, <b>4</b>, and <b>5</b>, but 4-fold less potent than TEL (<b>2</b>) against a mutant <i>E. coli</i> A2058G strain

Desmethyl Macrolides: Synthesis and Evaluation of 4,8-Didesmethyl Telithromycin

There is an urgent need for novel sources of antibiotics to address the incessant and inevitable onset of bacterial resistance. To this end, we have initiated a structure-based drug design program that features a desmethylation strategy (i.e., replacing methyl groups with hydrogens). Herein, we report the total synthesis, molecular modeling, and biological evaluation of 4,8-didesmethyl telithromycin (<b>5</b>), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (<b>2</b>), which is an FDA-approved semisynthetic derivative of erythromycin (<b>1</b>). We found <b>5</b> to be eight times more active than previously prepared 4,8,10-tridesmethyl congener (<b>3</b>) and two times more active than 4,10-didesmethyl regioisomer (<b>4</b>) in MIC assays. While less potent than telithromycin (<b>2</b>) and paralleling the observations made in the previous study of 4,10-didesmethyl analogue (<b>4</b>), the inclusion of a single methyl group improves biological activity, thus supporting its role in antibiotic activity

Desmethyl Macrolides: Synthesis and Evaluation of 4,10-Didesmethyl Telithromycin

Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling, and biological evaluation of 4,10-didesmethyl telithromycin (<b>4</b>), a novel desmethyl analogue of the third-generation drug telithromycin (<b>2</b>). Telithromycin is an FDA-approved ketolide antibiotic derived from erythromycin (<b>1</b>). We found 4,10-didesmethyl telithromycin (<b>4</b>) to be four times more active than previously prepared 4,8,10-tridesmethyl congener (<b>3</b>) in MIC assays. While less potent than telithromycin (<b>2</b>), the inclusion of the C-8 methyl group has improved biological activity, suggesting that it plays an important role in antibiotic function

Desmethyl Macrolides: Synthesis and Evaluation of 4,10-Didesmethyl Telithromycin

Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling, and biological evaluation of 4,10-didesmethyl telithromycin (<b>4</b>), a novel desmethyl analogue of the third-generation drug telithromycin (<b>2</b>). Telithromycin is an FDA-approved ketolide antibiotic derived from erythromycin (<b>1</b>). We found 4,10-didesmethyl telithromycin (<b>4</b>) to be four times more active than previously prepared 4,8,10-tridesmethyl congener (<b>3</b>) in MIC assays. While less potent than telithromycin (<b>2</b>), the inclusion of the C-8 methyl group has improved biological activity, suggesting that it plays an important role in antibiotic function

Synthesis of 5-Fluoro- and 5-Hydroxymethanoprolines via Lithiation of <i>N</i>-BOC-methanopyrrolidines. Constrained C^γ-Exo and C^γ-Endo Flp and Hyp Conformer Mimics

Proline derivatives with a C^γ-exo pucker typically display a high amide bond trans/cis (<i>K</i>_T/C) ratio. This pucker enhances n→π* overlap of the amide oxygen and ester carbonyl carbon, which favors a trans amide bond. If there were no difference in n→π* interaction between the ring puckers, then the correlation between ring pucker and <i>K</i>_T/C might be broken. To explore this possibility, proline conformations were constrained using a methylene bridge. We synthesized discrete gauche and anti 5-fluoro- and 5-hydroxy-<i>N</i>-acetylmethanoproline methyl esters from 3-syn and 3-anti fluoro- and hydroxymethanopyrrolidines using directed α-metalation to introduce the α-ester group. NBO calculations reveal minimal n→π* orbital interactions, so contributions from other forces might be of greater importance in determining <i>K</i>_T/C for the methanoprolines. Consistent with this hypothesis, greater trans amide preferences were found in CDCl₃ for anti isomers en-MetFlp and en-MetHyp (72–78% trans) than for the syn stereoisomers ex-MetFlp and ex-MetHyp (54–67% trans). These, and other, <i>K</i>_T/C results that we report here indicate how substituents on proline analogues can affect amide preferences by pathways other than ring puckering and n→π* overlap and suggest that caution should be exercised in assigning enhanced pyrrolidine C^γ-exo ring puckering based solely on enhanced trans amide preference

Desmethyl Macrolides: Synthesis and Evaluation of 4‑Desmethyl Telithromycin

Novel sources of antibiotics are needed to address the serious threat of bacterial resistance. Accordingly, we have launched a structure-based drug design program featuring a desmethylation strategy wherein methyl groups have been replaced with hydrogens. Herein we report the total synthesis, molecular modeling, and biological evaluation of 4-desmethyl telithromycin (<b>6</b>), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (<b>2</b>) and our final analogue in this series. While 4-desmethyl telithromycin (<b>6</b>) was found to be equipotent with telithromycin (<b>2</b>) against wild-type bacteria, it was 4-fold less potent against the A2058G mutant. These findings reveal that strategically replacing the C4-methyl group with hydrogen (i.e., desmethylation) did not address this mechanism of resistance. Throughout the desmethyl series, the sequential addition of methyls to the 14-membered macrolactone resulted in improved bioactivity. Molecular modeling methods indicate that changes in conformational flexibility dominate the increased biological activity; moreover, they reveal <b>6</b> adopts a different conformation once bound to the A2058G ribosome, thus impacting noncovalent interactions reflected in a lower MIC value. Finally, fluorescence polarization experiments of <b>6</b> with <i>E. coli</i> ribosomes confirmed <b>6</b> is indeed binding the ribosome