Optimized syntheses of ()-5-(2-ethoxyphenyl)--(3-(methylsulfonyl)allyl)-1-pyrazole-3-carboxamide (RA-0002034, ), a promising antiviral covalent cysteine protease inhibitor lead, were developed. The syntheses avoid the contamination of with the inactive cyclic dihydropyrazolo[1,5-]pyrazin-4(5)-one , which is formed by the intramolecular aza-Michael reaction of the vinyl sulfone warhead under basic conditions and slowly at pH 7.4 in phosphate buffer.
View Article and Find Full Text PDFMalaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold.
View Article and Find Full Text PDFAntimicrobial 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).
View Article and Find Full Text PDFMalaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold.
View Article and Find Full Text PDFLeishmaniasis is a collection of diseases caused by more than 20 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.
View Article and Find Full Text PDFTarget 2035, an international federation of biomedical scientists from the public and private sectors, is leveraging 'open' principles to develop a pharmacological tool for every human protein. These tools are important reagents for scientists studying human health and disease and will facilitate the development of new medicines. It is therefore not surprising that pharmaceutical companies are joining Target 2035, contributing both knowledge and reagents to study novel proteins.
View Article and Find Full Text PDFAlzheimer's disease is imposing a growing social and economic burden worldwide, and effective therapies are urgently required. One possible approach to modulation of the disease outcome is to use small molecules to limit the conversion of monomeric amyloid (Aβ42) to cytotoxic amyloid oligomers and fibrils. We have synthesized modulators of amyloid assembly that are unlike others studied to date: these compounds act primarily by sequestering the Aβ42 monomer.
View Article and Find Full Text PDFOne aspirational goal of computational chemistry is to predict potent and drug-like binders for any protein, such that only those that bind are synthesized. In this Roadmap, we describe the launch of Critical Assessment of Computational Hit-finding Experiments (CACHE), a public benchmarking project to compare and improve small molecule hit-finding algorithms through cycles of prediction and experimental testing. Participants will predict small molecule binders for new and biologically relevant protein targets representing different prediction scenarios.
View Article and Find Full Text PDFTwenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function.
View Article and Find Full Text PDFComplexes incorporating a threading anthraquinone intercalator with pyrrole lexitropsin and platinum(II) moieties attached were developed with the goal of generating novel DNA binding modes, including the targeting of AT-rich regions in order to have high cytotoxicities. The binding of the complexes to DNA has been investigated and profiles surprisingly similar to that for cisplatin were observed; the profiles were different to those for a complex lacking the pyrrole lexitropsin component. The lack of selective binding to AT-rich regions suggests the platinum binding was dominating the sequence selectivity, and is consistent with the pyrrole lexitropsin slowing intercalation.
View Article and Find Full Text PDFThe Open Source Malaria (OSM) consortium is developing compounds that kill the human malaria parasite, , by targeting ATP4, an essential ion pump on the parasite surface. The structure of ATP4 has not been determined. Here, we describe a public competition created to develop a predictive model for the identification of ATP4 inhibitors, thereby reducing project costs associated with the synthesis of inactive compounds.
View Article and Find Full Text PDFThere is an increasingly urgent need for new antibiotics, yet there is a significant and persistent economic problem when it comes to developing such medicines. The problem stems from the perceived need for a "market" to drive commercial antibiotic development. In this article, we explore abandoning the market as a prerequisite for successful antibiotic research and development.
View Article and Find Full Text PDFCOVID-19 has resulted in huge numbers of infections and deaths worldwide and brought the most severe disruptions to societies and economies since the Great Depression. Massive experimental and computational research effort to understand and characterize the disease and rapidly develop diagnostics, vaccines, and drugs has emerged in response to this devastating pandemic and more than 130 000 COVID-19-related research papers have been published in peer-reviewed journals or deposited in preprint servers. Much of the research effort has focused on the discovery of novel drug candidates or repurposing of existing drugs against COVID-19, and many such projects have been either exclusively computational or computer-aided experimental studies.
View Article and Find Full Text PDFThe coordination chemistry of N-functionalised cyclam ligands has a rich history, yet cyclam derivatives with pendant alkynes are largely unexplored. This is despite the significant potential and burgeoning application of N-propargyl cyclams and related compounds in the creation of diversely functionalised cyclam derivatives via copper-catalysed azide-alkyne 'click' reactions. Herein we describe single crystal X-ray diffraction and spectroscopic investigations of the coordination chemistry of copper(ii) complexes of cyclam derivatives with between 1 and 4 pendant alkynes.
View Article and Find Full Text PDFIn 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 global collaborative efforts.
View Article and Find Full Text PDFWe have discovered and studied a -substitution reaction in a biologically important heterocyclic ring system. Conditions that favor the -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.
View Article and Find Full Text PDFThe 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).
View Article and Find Full Text PDFThere is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases.
View Article and Find Full Text PDFSix to swear by! Society needs effective and affordable medicines. We currently have at our disposal essentially one system to discover and develop drugs, and there are many areas where this system struggles to deliver, for example to combat antimicrobial resistance, or tropical diseases, or dementia. It is sensible to cultivate alternative, competing approaches to drug discovery and development.
View Article and Find Full Text PDFGreat 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.
View Article and Find Full Text PDFSociety urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community.
View Article and Find Full Text PDFThe 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 (IC) of new chemical entities (NCEs) during early stages of drug design and development.
View Article and Find Full Text PDFEumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungus Madurella mycetomatis. A combination of surgery and prolonged medication is needed to treat this infection with a success rate of only 30%. There is, therefore, an urgent need to find more effective drugs for the treatment of this disease.
View Article and Find Full Text PDFWe recently reported the discovery of nontoxic cyclam-derived compounds that are active against drug-resistant Mycobacterium tuberculosis. In this paper we report exploration of the structure-activity relationship for this class of compounds, identifying several simpler compounds with comparable activity. The most promising compound identified, possessing significantly improved water solubility, displayed high levels of bacterial clearance in an in vivo zebrafish embryo model, suggesting this compound series has promise for in vivo treatment of tuberculosis.
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