Medicinal Chemistry

Protozoan parasites are inhibited by 2,4-diaminopyrimidines and azabicyclo-nonanes. A series of fused hybrids were created and tested in vitro against malaria tropica and sleeping sickness pathogens. Compound activities and selectivities were heavily influenced by the substitution pattern of both ring systems as well as the position of the nitrogen atom in the bicycles. The most promising hybrids of 3-azabicyclo-nonane and 2-aminopyrimidine demonstrated submicromolar activity and high selectivity against P. falciparum NF54. A hybrid with pyrrolidino substitutions of the 2-azabicyclo-nonane and the pyrimidine moiety showed promising activity against the multiresistant P. falciparum K1 strain. A couple of hybrids of 2-azabicyclo-nonanes and 2-pyrimidines showed high activity and selectivity against Trypanosoma brucei rhodesiense.

Antimicrobial resistance is spreading globally, making healthcare specialists fear "a return to the dark age of medicine". Great efforts are being made to develop new antimicrobials or to repurpose discontinued or shelved drugs to be used against resistant "superbugs". Antibiotic resistance develops in part because the antibiotics we use kill the bacteria. However, this creates a strong selection pressure: a resistant bacterium multiplies while its non-resistant competitors die. As a result, resistance will emerge quickly in the presence of that antibiotic. Another option is to simply disable bacteria, reducing their ability to infect the host. In other words, rather than inhibiting bacterial viability, Bacterial pathogenesis and infectivity are mediated by virulence factors. Collagenases are virulence factors produced by a variety of bacteria, including Clostridium, Bacillus, Vibrio, and Pseudomonas. These enzymes are among the most efficient collagen degraders, and they play an important role in host colonisation. Because of their critical roles in the infection process, they are an important target for the development of new anti-infective agents. The inhibitory activity of 77 compounds on collagenase A was experimentally evaluated using a fluorescence resonance energy-transfer assay in a primary screening.