A Structural View on Medicinal Chemistry Strategies against Drug Resistance.

The natural phenomenon of drug resistance is a widespread issue that hampers the performance of drugs in many major clinical indications. Antibacterial and antifungal drugs are affected, as well as compounds for the treatment of cancer, viral infections, or parasitic diseases. Despite the very diverse set of biological targets and organisms involved in the development of drug resistance, the underlying molecular mechanisms have been identified to understand the emergence of resistance and to overcome this detrimental process.

Pseudouridimycin: The First Nucleoside Analogue That Selectively Inhibits Bacterial RNA Polymerase.

Seek, and ye shall find: After years of focusing research on synthetic antibiotics out of fear that all the useful natural ones had already been found, a novel antibacterial compound has been discovered through conventional microbial extract screening. The broad-spectrum nucleoside-analogue inhibitor pseudouridimycin is selective for bacterial RNA polymerase and elicits very low resistance rates.

Targeting Antibiotic Resistance.

Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human-pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last-resort antibiotics have lost their power.

Organocatalytic asymmetric annulation of 1,3-bis(alkoxycarbonyl)buta-1,3-dienes and aldehydes.

Asymmetric organocatalytic annulation of E/Z isomeric mixtures of bis(alkyl carboxylate)buta-1,3-dienes and aldehydes has been realized via enamine catalysis. In the presence of α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether, excellent stereo- and enantioselectivities were achieved for a broad spectrum of substrates.

Synthesis of key fragments of leiodelide A.

The synthesis of all key fragments of the marine macrolide leiodelide A is described. The polyoxygenated northern subunit is derived from d-xylose, while the southern subunit is rapidly assembled via an aldol reaction and Horner-Wadsworth-Emmons olefination. This highly convergent approach will allow for rapid modification and assembly of several isomers of leiodelide A, which may be necessary considering the assignment of leiodelide B has been previously shown to be incorrect.