Medicinal Chemistry Group

Research


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Our research covers a range of medicinal chemistry and chemical biology areas focused on malaria, TB, HIV and filariasis. More recently we have also initiated medicinal chemistry programmes in neuropathic pain and pancreatitis.

  • Malaria

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    Isoquine

    The synthesis of quinoline containing antimalarials based on the concepts of drug-metabolism design and drug metabolism resistance. This research approach led to the discovery of a novel 4-aminoquinoline, Isoquine,1,2 a drug entering clinical trials in man in 2008 in partnership with GSK and the Medicines for Malaria Venture (MMV) (Figure 1).

    Fig. 1 Process Development Chemistry and Structure of Antimalarial Clinical Candidate Isoquine (GSK369796).

    This work is in collaboration with Professor Steve Ward at the Liverpool School of Tropical Medicine.

    This work is part of the Medicines for Malaria Venture

    1. O’Neill, P. M.; Park, B. K et al. Candidate Selection and Preclinical Evaluation of N-tert-Butyl Isoquine (GSK369796), An Affordable and Effective 4-Aminoquinoline Antimalarial for the 21st Century. Journal of Medicinal Chemistry 2009, 52, 1408-1415. DOI: 10.1021/jm8012618

    2. O’Neill, P. M.; Shone, A. E. et al. Synthesis, Antimalarial Activity, and Preclinical Pharmacology of a Novel Series of 4 ‘-Fluoro and 4 ‘-Chloro Analogues of Amodiaquine. Identification of a Suitable “Back-Up” Compound for N-tert-Butyl Isoquine. Journal of Medicinal Chemistry 2009, 52, 1828-1844. DOI: 10.1021/jm8012757


    Medicinal chemistry of Novel Peroxide Antimalarials (EU FP6, MMV, BBSRC)

    Whilst artemisinin and its derivatives remain the current cornerstone of antimalarial therapy, first-generation analogues, for example, artemether and artesunate, have poor oral bioavailability. Additionally, the emergence of artemisinin-resistant strains of parasite is cause for increasing concern (Figure 2).

    Fig. 2 Synthetic Approach to 1,2,4,5-Tetraoxane Antimalarials and First Identified Lead Compound in Series

    In light of this, there is an urgent need to develop alternative medicines that can overcome these drawbacks while maintaining the same impressive efficacy as artemisinin. Our initial work in this area led to the tetraoxane RKA182 that was candidate selected in 2011 for preclinical development.1-3 Although this molecule had characteristics which would enable treatment of malaria as part of a three day dosage regimen, the new goal for malaria treatment is to achieve single dose cure of malaria. Thus, more recent work, funded by the Medicines for Malaria Venture (MMV), has focused on a second-generation late lead tetraoxane E209 with a significantly longer half-life. The aim is to deliver a pre-clinical candidate by the end of 2016. If successful, such a molecule could hold potential as a single dose cure for malaria.

    This work is in collaboration with Professor Steve Ward at the Liverpool School of Tropical Medicine.

    1. O’Neill, P. M.; Amewu, R. K. et al. Identification of a 1,2,4,5-Tetraoxane Antimalarial Drug-Development Candidate (RKA 182) with Superior Properties to the Semisynthetic Artemisinins. Angewandte Chemie-International Edition 2010, 49, 5693-5697. DOI: 10.1002/anie.201001026

    2. Marti, F.; Chadwick, J. et al. Second generation analogues of RKA182: synthetic tetraoxanes with outstanding in vitro and in vivo antimalarial activities. Medchemcomm 2011, 2, 661-665. DOI: 10.1039/c1md00102g

    3. Chadwick, J.; Amewu, R. K. et al. Antimalarial Mannoxanes: Hybrid Antimalarial Drugs with Outstanding Oral Activity Profiles and A Potential Dual Mechanism of Action. Chemmedchem 2011, 6, 1357-1361. DOI: 10.1002/cmdc.201100196


    Targeting PfNDH2 (Wellcome Trust Seeding Drug Discovery)

    As part of a Wellcome Trust Seeding Drug Discovery award (2008, 1.4 million with LSTM) we have developed an assay for the alternative complex 1 (PfNDH2) of Plasmodium falciparum suitable for use in an HTS screening campaign. Following a cheminformatics approach to compound selection and in collaboration with BioFocus (Cambridge) we have screened over 15, 000 compounds and from this approach identified several novel scaffolds for optimization. We have proceeded from hit to lead optimization and have identified a novel series of quinolones that not only inhibit the malarial enzyme PfNDH2 in the nanomolar region but also express antimalarial activity in the low nanomolar region with oral activity in the mouse model of malaria (Figure 3).1-4

     

    Fig. 3 Hit to Lead Optimisation to Produce Nanomolar Inhibitors of PfNDH2

    This work is in collaboration with Professor Steve Ward and Professor Giancarlo Biagini at the Liverpool School of Tropical Medicine.

    1. Pidathala, C.; et al. Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2). Journal of Medicinal Chemistry 2012, 55, 1831-1843. DOI: 10.1021/jm201179h

    2. Leung, S. C.; et al. Identification, Design and Biological Evaluation of Heterocyclic Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2). Journal of Medicinal Chemistry 2012, 55, 1844-1857. DOI: 10.1021/jm201184h

    3. Fisher, N.; et al.. Cytochrome b Mutation Y268S Conferring Atovaquone Resistance Phenotype in Malaria Parasite Results in Reduced Parasite bc(1) Catalytic Turnover and Protein Expression. Journal of Biological Chemistry 2012, 287, 9731-9741. DOI: 10.1074/jbc.M111.324319

    4. Biagini, G. et al., Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain, Proc Nat Acad Sci USA, 2012, 109, 8298-8303. DOI: 10.1073/pnas.1205651109 


    New Quinolone Inhibitors Targeting the Cytochrome bc1 Complex of Plasmodium falciparum

    Cytochrome bc1 complex is a multisubunit membrane protein complex which is one of the fundamental components of respiratory processes. The enzyme catalyses electron transfer from ubiquinol to cytochrome c and couples this process to the translocation of protons across the membrane for various cellular processes including ATP synthesis. Each functional unit of the homodimeric complex consists of three catalytic subunits: cytochrome b with two b type hemes, cytochrome c1 with one c type heme, and the Rieske protein containing a [2Fe-2S] cluster. (Figure 4).

    Fig. 4 Cytochrome b subunit of bc1 MIM-Mitochondrial inner membrane, IMS-Intermembrane space.

    The bc1 complex is a validated target for antimalarial drug discovery as exemplified by the drug development of atovaquone and more recently by the discovery of pyridone based inhibitors of this complex. The latter agents are in advanced preclinical stages of development. Recently, studies at Liverpool have confirmed that the acridinedione derivatives such as floxacrine can also selectively (nM range) inhibit parasite mitochondrial function. Indeed, these novel inhibitors are ~5000 fold more selective for P. falciparum bc1 over human bc1. This selectivity is some 200 fold higher than that seen with atovaquone (Biagini et al., submitted). Furthermore, studies performed using yeast with mutated bc1, reveal that acridinedione derivatives preferentially bind the Qo pocket of the b cytochrome (Biagini et al., submitted). Based on these observations Neil Berry’s group have initiated homology based modelling studies of a range of inhibitors. Figure 5 depicts analogue docked into the active site. Ultimately, we plan to use this model in a rationale drug design approach to novel quinoline inhibitors.

    Fig. 5. Dihydroacridinedione docking into P. falciparum cytochrome b (Qo). Docking of the dihydroacridinediones floxacrine (not shown) and WR249685 (11) was energetically favourable (binding energy -8.1 kcal/mol, estimated Ki ~ 1.14 µM). Right hand panel shows Qo-site residues predicted to be within 4 Å of the bound WR249685 (most energetically favourable conformation).

    This work is in collaboration with Professor Samar Hasnain and Dr Svetlana Antonyuk from the Institute of Integrative Biology.

    1. Capper, M. J., O'Neill, P. M., Fisher, N., Strange, R. W., Moss, D., Ward, S. A., . . . Antonyuk, S. V. (2015). Antimalarial 4(1H)-pyridones bind to the Q(i) site of cytochrome bc(1). PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 112(3), 755-760. DOI: 10.1073/pnas.1416611112


    Washington University St Louis/UOL Link – The MEP Pathway and the Development of Inhibitors as Novel Antimalarials (CDI, St Louis, USA)

    Recently, we have set up an international collaboration with Washington University in St Louis USA with Dr Audrey Odom. Preliminary data in the Odom lab has indicated that a particular enzyme of isoprenoid biosynthesis (IspD) is essential for the development of the malaria parasite, and additional studies have indicated that this enzyme can be inhibited by small molecules.1 Currently we have a programme directed at the synthesis of inhibitors of the MEP pathway and in addition to targeting ISPD (Figure 6) we are also examining new approaches to targeting ISPC and ISPF on this pathway.

    Fig. 6. Molecular docking of 1R,3S-MMV008138 in the active site of ISPD.

    1. Armstrong, C.M. et al. ACS Infect. Dis. 2015, 1, 157-167. DOI: 10.1021/id500047s

  • Tuberculosis

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    Lead Series Development & Optimisation of a New Drug Against Active and Latent Tuberculosis (MRC DPFS)

    A major failure of current tuberculosis (TB) therapies is that they predominantly target replicating Mycobacterium tuberculosis (Mtb) but are unable to sterilize slow growing (dormant) Mtb, leading to protracted treatment regimes and the development of drug resistance. We propose to generate a new drug against TB that is able to mitigate the shortcomings of current therapies, leading to improved treatment outcomes. Our strategy is to target the Mtb respiratory chain, specifically NADH:menaquinone oxidoreductase (ndh) (Figure 7). This target is essential for the survival of replicating, dormant and drug resistant Mtb, and it is absent in humans. Over the past 2 years we have successfully progressed from target validation/hit identification to the discovery of novel potent (nM) inhibitors of ndh with corresponding potent (nM) in vitro sterilization activity against replicating and dormant Mtb. We have received funding for a 1 million pound grant from the MRC to perform lead optimisation of our quinolone antitubercular compounds (Figure 8). The project is in collaboration with GSK, Tres Cantos, Madrid, Spain.

    Fig. 7. Cartoon representation of the electron transport chain in Mycobacterium tuberculosis. We are targeting the Ndh component.

    Fig. 8. High throughput screening triage, informed by chemoinformatics, targeting the Ndh component of the electron transport chain of Mycobacterium tuberculosis. We have identified antituberculosis compounds which have now entered medicinal chemistry optimisation

    This work is performed with Professor Steve Ward and Professor Giancarlo Biagini from the Liverpool School of Tropical Medicine.

     

  • Filiriasis

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    Medicinal Chemistry of Anti-Wolbachia Drugs (LSTM, Bill and Melinda Gates Foundation)

    Our drug discovery and development portfolio also includes a new Gates funded programme on novel anti-Wolbachia drugs for lymphatic filariasis. This programme, in collaboration with Astra Zeneca, has revealed over ten new antibacterial chemotypes primed for medicinal chemistry optimization and we are actively engaged in hit to lead optimization.

    This work is in collaboration with Professor Steve Ward and Professor Mark Taylor at the Liverpool School of Tropical Medicine and is part of the AWOL consortium.

  • Neuropathic Pain

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    Medicinal Chemistry of Neuropathic Pain (MRC DPFS)

    Positive Allosteric Modulators of Alpha 1 Glycine Receptors. Our recently funded MRC DPFS (£1.1 million) project addresses the longstanding unmet need of chronic pain. This debilitating condition affects about 20% of adults in Europe and in the USA. We have successfully progressed from medicinal chemistry target validation/hit identification to the discovery of a novel class of compounds with selective pM/low nM positive allosteric modulating activity at α1-glycine receptors (Figure 9). Such an action compensates for the loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord, which plays a key role in central pain sensitisation.

    Fig. 9 Positive Allosteric Modulators of Alpha 1 Glycine Receptors together with their calulated steric and electrostatic fields.

    This work is in collaboration with Prof. Martin Leuwer from the Institute of Translational Medicine.

     

  • Chemical Biology

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    Chemical biology (MRC, BBSRC, EU)

    Areas include, The biomimetic Fe(II) chemistry and EPR spectroscopy of new peroxide containing antimalarials; Mechanism based design of novel endoperoxide protease inhibitor pro-drugs; Application of proteomic techniques to identifying (i) the cellular targets of the artemisinin using biotinylated probe molecules (ii) P450s responsible for resistance to pyrethroid insecticides (Figure 10) using Click methodologies and rational probe design and synthesis.1

    Fig. 10 Chemical biology of pyrethroid insecticides.

    This work is in collaboration with Dr Mark Paine and Dr Hanafy Ismail at the Liverpool School of Tropical Medicine.

    1. Ismail, H. M.; O'Neill, P. Met al. Pyrethroid activity-based probes for profiling cytochrome P450 activities associated with insecticide interactions. Proc Nat Acad Sci USA 2013, 110, 19766-19771.
  • Cyclophilins as a Drug Target

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    Lead Series Development & Optimisation of a New Drug Against Acute Pancreatitis

    The mitochondrial permeability transition pore (MPTP) plays an important role in damage-induced cell death, and agents inhibiting this pore may have a therapeutic potential for treating human conditions such as ischemia/reperfusion injury, trauma, and neurodegenerative diseases.

    Opening of the MPTP causes mitochondrial dysfunction and necrosis in acute pancreatitis, a condition without specific drug treatment. Cyclophilin D (CypD) is a mitochondrial matrix peptidyl-prolyl isomerase that regulates the MPTP and is a drug target for acute pancreatits. We have synthesized urea-based small molecule inhibitors of cyclophilins and tested them against CypD using binding and isomerase activity assays. Our most potent compound to date shows enzymatic inhibition in the nanomolar range and is undergoing further optimisation as a novel small molecule agent against acute pancreatitis (Figure 11).1

    Fig. 11 Design of potent inhibitors of Cyclophilin D

    This work is in collaboration with Prof. Robert Sutton from the Institute of Translational Medicine and Prof. Lu-Yun Lian from the Instute of Integrative Biology.

    1. Shore, E. R., Awais, M., Kershaw, N. M., Gibson, R. R., Pandalaneni, S., Latawiec, D., Sutton, R. et. al. (2016). Small Molecule Inhibitors of Cyclophilin D to Protect Mitochondrial Function as a Potential Treatment for Acute Pancreatitis. Journal of Medicinal Chemistry, 59(6), 2596-2611.

  • Cryptococcus

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    Design, Synthesis and Biological Evaluation of β-tubulin binding benzimidazole like compounds for the treatment of Cryptococcus neoformans

    Cryptococcus neoformans is yeast like fungus that occurs in both plants and animals. It is composed of two varieties; C. neoformans v. neoformans and C.n.v. grubii , as well as an extinct form C.n.v gattii.1 In most cases it causes an infection of the lungs, however it can cause fungal meningitis and encephalitis, which is particularly problematic as a secondary infection in immunosuppressed patients, such as those suffering from AIDS.2 It is estimated that there are 1 million cases of cryptococcal meningitis worldwide each year, of which 625,000 result in death.3

    Fig. 12 Scanning Electron Micrograph of the Cryptococcus neoformans yeast producing spores.4

    Current treatments for the disease (amphotericin B, flucytosine and fluconazole) are associated with several issues including toxicity, poor activity and supply problems.5 Evidently, new compounds with improved Drug Metabolism and Pharmacokinetic (DMPK) properties need to be generated for use in the treatment of cryptococcal infections.

    The benzimidazole class of compounds has been historically used to treat helminth infections in humans and includes compounds such as albendazole and flubendazole. However, it has been noted that they also show good in vitro potency against C. neoformans. Benzimidazoles bind to the β-tubulin subunit of microtubules and cause disruption of the mitosis pathway. Furthermore, characterisation of the β-tubulin genes of Cryptococcus neoformans has been achieved and it was found TUB1 is the primary target of the benzimidazole class of compounds.6

    The medicinal chemistry aspect of this project will involve the exploration of the SAR of both flubendazole and albendazole, in order to improve DMPK properties and the safety profile. This will also utilise predictive models to help target the design of albendazole and flubendazole analogues. Any analogues that are produced will be assessed for in vitro activity, in collaboration with Prof. William Hope (University of Liverpool, Institute of Translational Medicine), and will allow for redesign of the compounds to understand the SAR and improve DMPK properties throughout the project. Selected compounds demonstrating suitable potency and DMPK properties will undergo in vivo PK/PD experiments in the murine model of C. neoformans infection.

    Fig. 13 Strategy for exploration of the SAR of flubendazole and albendazole
    1. K. J. Kwon-Chung and J. E. Bennett, American Journal of Epidemiology, 1984, 120, 123-130
    2. J. N. Steenbergen and A. Casadevall, Journal of Clinical Microbiology, 2000, 38, 1974-1976.
    3. CDC, Centre for Disease Control and Prevention, 2014.
    4. C. Xue and K. Carroll, Live Science, 2013.
    5. S. J. Antony, A. Patel and J. Leonard, Journal of the National Medical Association, 1997, 89, 694-695.
    6. M. C. Cruz, M. S. Bartlett and T. D. Edlind, Antimicrobial Agents and Chemotherapy, 1994, 38, 378-380.
  • Romark Collaboration

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    Romark

     

     

    Romark is a pharmaceutical company committed to the discovery, development and commercialization of innovative small molecules for treating infectious diseases and cancers. 

    Medicinal chemistry at the University of Liverpool has enjoyed a very successful collaboration over a number of years. Dr Andrew Stachulski has provided his ‌personal reflections on the Romark Collaboration.

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