Small molecule drug metabolite synthesis and identification: why, when and how?

The drug discovery and development process encompasses the interrogation of metabolites arising from the biotransformation of drugs. Here we look at why, when and how metabolites of small-molecule drugs are synthesised from the perspective of a specialist contract research organisation, with particular attention paid to projects for which regulatory oversight is relevant during this journey. To illustrate important aspects, we look at recent case studies, trends and learnings from our experience of making and identifying metabolites over the past ten years, along with with selected examples from the literature.

Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant .

Antimicrobial resistance (AMR) is widely acknowledged as one of the most serious public health threats facing the world, yet the private sector finds it challenging to generate much-needed medicines. As an alternative discovery approach, a small array of diarylimidazoles was screened against the ESKAPE pathogens, and the results were made publicly available through the Open Source Antibiotics (OSA) consortium (https://github.com/opensourceantibiotics).

Ivermectin metabolites reduce Anopheles survival.

Ivermectin mass drug administration to humans or livestock is a potential vector control tool for malaria elimination. The mosquito-lethal effect of ivermectin in clinical trials exceeds that predicted from in vitro laboratory experiments, suggesting that ivermectin metabolites have mosquito-lethal effect. The three primary ivermectin metabolites in humans (i.

Biotransformation: Impact and Application of Metabolism in Drug Discovery.

Biotransformation has a huge impact on the efficacy and safety of drugs. Ultimately the effects of metabolism can be the lynchpin in the discovery and development cycle of a new drug. This article discusses the impact and application of biotransformation of drugs by mammalian systems, microorganisms, and recombinant enzymes, covering active and reactive metabolites, the impact of the gut microbiome on metabolism, and how insights gained from biotransformation studies can influence drug design from the combined perspectives of a CRO specializing in a range of biotransformation techniques and pharma biotransformation scientists.

Microbial biotransformation - an important tool for the study of drug metabolism.

Metabolite identification is an integral part of both preclinical and clinical drug discovery and development. Synthesis of drug metabolites is often required to support definitive identification, preclinical safety studies and clinical trials. Here we describe the use of microbial biotransformation as a tool to produce drug metabolites, complementing traditional chemical synthesis and other biosynthetic methods such as hepatocytes, liver microsomes and recombinant human drug metabolizing enzymes.

γ-Heptalactone is an endogenously produced quorum-sensing molecule regulating growth and secondary metabolite production by Aspergillus nidulans.

Microbes monitor their population density through a mechanism termed quorum sensing. It is believed that quorum-sensing molecules diffuse from the microbial cells and circulate in the surrounding environment as a function of cell density. When these molecules reach a threshold concentration, the gene expression of the entire population is altered in a coordinated manner.

Genetic engineering in Streptomyces roseosporus to produce hybrid lipopeptide antibiotics.

Daptomycin is a lipopeptide antibiotic produced by a nonribosomal peptide synthetase (NRPS) in Streptomyces roseosporus. The holoenzyme is composed of three subunits, encoded by the dptA, dptBC, and dptD genes, each responsible for incorporating particular amino acids into the peptide. We introduced expression plasmids carrying dptD or NRPS genes encoding subunits from two related lipopeptide biosynthetic pathways into a daptomycin nonproducing strain of S.

Hydroxychloroquine is much less active than chloroquine against chloroquine-resistant Plasmodium falciparum, in agreement with its physicochemical properties.

The 4-aminoquinoline drug hydroxychloroquine (HCQ) is reported to be as active as chloroquine (CQ) against falciparum malaria, and less toxic. Existing prophylactic regimens for areas where there is CQ-resistant malaria recommend CQ with proguanil as an alternative where none of the three preferred regimens (atovaquone-proguanil, doxycycline or mefloquine) is thought suitable. In such cases, toxicity is likely when CQ-proguanil is administered to persons being treated for autoimmune disease with daily HCQ.

Indole and beta-carboline alkaloids from Geissospermum sericeum.

The indole alkaloid geissoschizoline (1) and two new derivatives, geissoschizoline N(4)-oxide (2) and 1,2-dehydrogeissoschizoline (3), were obtained from the bark of Geissospermum sericeum together with the beta-carboline alkaloid flavopereirine (4). The in vitro antiplasmodial activity of these compounds was evaluated in chloroquine-resistant (K1) and chloroquine-sensitive (T9-96) Plasmodium falciparum. Their cytotoxicity was determined in a human (KB) cell line.