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

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). Of the 18 compounds tested (at 32 µg/mL), 15 showed >90% growth inhibition activity against methicillin-resistant Staphylococcus aureus (MRSA) alone. In the subsequent hit-to-lead optimization of this chemotype, 147 new heterocyclic compounds containing the diarylimidazole and other core motifs were synthesized and tested against MRSA, and their structure-activity relationships were identified. While potent, these compounds have moderate to high intrinsic clearance and some associated toxicity. The best overall balance of parameters was found with OSA_975, a compound with good potency, good solubility, and reduced intrinsic clearance in rat hepatocytes. We have progressed toward the knowledge of the molecular target of these phenotypically active compounds, with proteomic techniques suggesting TGFBR1 is potentially involved in the mechanism of action. Further development of these compounds toward antimicrobial medicines is available to anyone under the licensing terms of the project.

Structure-Property Optimization of a Series of Imidazopyridines for Visceral Leishmaniasis.

Leishmaniasis is a collection of diseases caused by more than 20 Leishmania parasite species that manifest as either visceral, cutaneous, or mucocutaneous leishmaniasis. Despite the significant mortality and morbidity associated with leishmaniasis, it remains a neglected tropical disease. Existing treatments have variable efficacy, significant toxicity, rising resistance, and limited oral bioavailability, which necessitates the development of novel and affordable therapeutics. Here, we report on the continued optimization of a series of imidazopyridines for visceral leishmaniasis and a scaffold hop to a series of substituted 2-(pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles with improved absorption, distribution, metabolism, and elimination properties.

An Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials.

The Open Source Malaria (OSM) consortium is developing compounds that kill the human malaria parasite, Plasmodium falciparum, by targeting PfATP4, an essential ion pump on the parasite surface. The structure of PfATP4 has not been determined. Here, we describe a public competition created to develop a predictive model for the identification of PfATP4 inhibitors, thereby reducing project costs associated with the synthesis of inactive compounds. Competition participants could see all entries as they were submitted. In the final round, featuring private sector entrants specializing in machine learning methods, the best-performing models were used to predict novel inhibitors, of which several were synthesized and evaluated against the parasite. Half possessed biological activity, with one featuring a motif that the human chemists familiar with this series would have dismissed as "ill-advised". Since all data and participant interactions remain in the public domain, this research project "lives" and may be improved by others.

Open science approaches to COVID-19.

In only a matter of months, the coronavirus disease of 2019 (COVID-19) has spread around the world. The global impact of the disease has caused significant and repeated calls for quick action towards new medicines and vaccines. In response, researchers have adopted open science methods to begin to combat this disease via global collaborative efforts. We summarise here some of those initiatives, and have created an updateable list to which others may be added. Though open science has previously been shown as an accelerator of biomedical research, the COVID-19 crisis has made openness seem the logical choice. Will openness persist in the discovery of new medicines, after the crisis has receded?

tele-Substitution Reactions in the Synthesis of a Promising Class of 1,2,4-Triazolo[4,3-a]pyrazine-Based Antimalarials.

We have discovered and studied a tele-substitution reaction in a biologically important heterocyclic ring system. Conditions that favor the tele-substitution pathway were identified: the use of increased equivalents of the nucleophile or decreased equivalents of base or the use of softer nucleophiles, less polar solvents, and larger halogens on the electrophile. Using results from X-ray crystallographic and isotope labeling experiments, a mechanism for this unusual transformation is proposed. We focused on this triazolopyrazine as it is the core structure of the in vivo active antiplasmodium compounds of Series 4 of the Open Source Malaria consortium.

Nonclassical Phenyl Bioisosteres as Effective Replacements in a Series of Novel Open-Source Antimalarials.

The replacement of one chemical motif with another that is broadly similar is a common method in medicinal chemistry to modulate the physical and biological properties of a molecule (i.e., bioisosterism). In recent years, bioisosteres such as cubane and bicyclo[1.1.1]pentane (BCP) have been used as highly effective phenyl mimics. Herein, we show the successful incorporation of a range of phenyl bioisosteres during the open-source optimization of an antimalarial series. Cubane (19) and closo-carborane (23) analogues exhibited improved in vitro potency against Plasmodium falciparum compared to the parent phenyl compound; however, these changes resulted in a reduction in metabolic stability; unusually, enzyme-mediated oxidation was found to take place on the cubane core. A BCP analogue (22) was found to be equipotent to its parent phenyl compound and showed significantly improved metabolic properties. While these results demonstrate the utility of these atypical bioisosteres when used in a medicinal chemistry program, the search to find a suitable bioisostere may well require the preparation of many candidates, in our case, 32 compounds.

The past, present and future of anti-malarial medicines.

Great progress has been made in recent years to reduce the high level of suffering caused by malaria worldwide. Notably, the use of insecticide-treated mosquito nets for malaria prevention and the use of artemisinin-based combination therapy (ACT) for malaria treatment have made a significant impact. Nevertheless, the development of resistance to the past and present anti-malarial drugs highlights the need for continued research to stay one step ahead. New drugs are needed, particularly those with new mechanisms of action. Here the range of anti-malarial medicines developed over the years are reviewed, beginning with the discovery of quinine in the early 1800s, through to modern day ACT and the recently-approved tafenoquine. A number of new potential anti-malarial drugs currently in development are outlined, along with a description of the hit to lead campaign from which it originated. Finally, promising novel mechanisms of action for these and future anti-malarial medicines are outlined.

Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical Entities.

The hERG (human ether-a-go-go-related gene) encoded potassium ion (K+) channel plays a major role in cardiac repolarization. Drug-induced blockade of hERG has been a major cause of potentially lethal ventricular tachycardia termed Torsades de Pointes (TdPs). Therefore, we presented a pharmacoinformatics strategy using combined ligand and structure based models for the prediction of hERG inhibition potential (IC50) of new chemical entities (NCEs) during early stages of drug design and development. Integrated GRid-INdependent Descriptor (GRIND) models, and lipophilic efficiency (LipE), ligand efficiency (LE) guided template selection for the structure based pharmacophore models have been used for virtual screening and subsequent hERG activity (pIC50) prediction of identified hits. Finally selected two hits were experimentally evaluated for hERG inhibition potential (pIC50) using whole cell patch clamp assay. Overall, our results demonstrate a difference of less than ±1.6 log unit between experimentally determined and predicted hERG inhibition potential (IC50) of the selected hits. This revealed predictive ability and robustness of our models and could help in correctly rank the potency order (lower µM to higher nM range) against hERG.