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Journal articleSymes OL, Ishikura H, Begg CS, et al., 2024,
Harnessing Oxetane and Azetidine Sulfonyl Fluorides for Opportunities in Drug Discovery.
, J Am Chem SocFour-membered heterocycles such as oxetanes and azetidines represent attractive and emergent design options in medicinal chemistry due to their small and polar nature and potential to significantly impact the physiochemical properties of drug molecules. The challenging preparation of these derivatives, especially in a divergent manner, has severely limited their combination with other medicinally and biologically important groups. Consequently, there is a substantial demand for mild and effective synthetic strategies to access new oxetane and azetidine derivatives and molecular scaffolds. Here, we report the development and use of oxetane sulfonyl fluorides (OSFs) and azetidine sulfonyl fluorides (ASFs), which behave as precursors to carbocations in an unusual defluorosulfonylation reaction pathway (deFS). The small-ring sulfonyl fluorides are activated under mild thermal conditions (60 °C), and the generated reactive intermediates couple with a broad range of nucleophiles. Oxetane and azetidine heterocyclic, -sulfoximine, and -phosphonate derivatives are prepared, several of which do not have comparable carbonyl analogs, providing new chemical motifs and design elements for drug discovery. Alternatively, a SuFEx pathway under anionic conditions accesses oxetane-sulfur(VI) derivatives. We demonstrate the synthetic utility of novel OSF and ASF reagents through the synthesis of 11 drug analogs, showcasing their potential for subsequent diversification and facile inclusion into medicinal chemistry programs. Moreover, we propose the application of the OSF and ASF reagents as linker motifs and demonstrate the incorporation of pendant groups suitable for common conjugation reactions. Productive deFS reactions with E3 ligase recruiters such as pomalidomide and related derivatives provide new degrader motifs and potential PROTAC linkers.
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Journal articleWorm D, Grabe G, Vieira de Castro G, et al., 2023,
Stapled Phd peptides inhibit Doc toxin induced growth arrest in Salmonella
, ACS Chemical Biology, Vol: 18, Pages: 2485-2494, ISSN: 1554-8929Bacterial toxin inhibition is a promising approach for overcoming antibiotic failure. In Salmonella, knock-out of the toxin Doc has been shown to significantly reduce the formation of antibiotic-tolerant persisters. Doc is a kinase that is inhibited in non-tolerant cells by its cognate antitoxin, Phd. In this work, we have developed first-in-class stapled peptide antitoxin mimetics based on the Doc inhibitory sequence of Phd. After making a series of substitutionsto improve bacterial uptake, we have identified a lead stapled Phd peptide able to counteract Doc toxicity in Salmonella. This provides an exciting starting point for the further development of therapeutic peptides capable of reducing antibiotic persistence in pathogenic bacteria.
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Conference paperSherin PS, Malde R, Mills T, et al., 2023,
Molecular rotors as tools to study downstream processes in mitochondria upon inhibition of protein-protein interactions
, 14th EBSA congress, Publisher: Springer, Pages: S157-S157, ISSN: 0175-7571 -
Journal articleHaque M, Flack T, Singh R, et al., 2023,
Aromatic oligoesters as novel helix mimetic scaffolds
, Bioorganic and Medicinal Chemistry, Vol: 87, ISSN: 0968-0896The design, synthesis, and conformational analysis of a novel aromatic oligoester helix mimetic scaffold is reported. A range of amino acid-type side-chain functionality can be readily incorporated into monomer building blocks over three facile synthetic steps. Analysis of representative dimers revealed a stable conformer capable of effective mimicry of a canonical α-helix and the scaffold was found to be surprisingly stable to degradation in aqueous solutions at acidic and neutral pH.
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Journal articleYahiya S, Saunders CN, Hassan S, et al., 2023,
A novel class of sulphonamides potently block malaria transmission by targeting a Plasmodium vacuole membrane protein
, Disease Models & Mechanisms, Vol: 16, Pages: 1-20, ISSN: 1754-8403Phenotypic cell-based screens are critical tools for discovering candidate drugs for development, yet identification of the cellular target and mode of action of a candidate drug is often lacking. Using an imaging-based screen, we recently discovered an N-[(4-hydroxychroman-4-yl)methyl]-sulphonamide (N-4HCS) compound, DDD01035881, that blocks male gamete formation in the malaria parasite life cycle and subsequent transmission of the parasite to the mosquito with nanomolar activity. To identify the target(s) of DDD01035881, and of the N-4HCS class of compounds more broadly, we synthesised a photoactivatable derivative, probe 2. Photoaffinity labelling of probe 2 coupled with mass spectrometry identified the 16 kDa Plasmodium falciparum parasitophorous vacuole membrane protein Pfs16 as a potential parasite target. Complementary methods including cellular thermal shift assays confirmed that the parent molecule DDD01035881 stabilised Pfs16 in lysates from activated mature gametocytes. Combined with high-resolution, fluorescence and electron microscopy data, which demonstrated that parasites inhibited with N-4HCS compounds phenocopy the targeted deletion of Pfs16 in gametocytes, these data implicate Pfs16 as a likely target of DDD01035881. This finding establishes N-4HCS compounds as being flexible and effective starting candidates from which transmission-blocking antimalarials can be developed in the future.
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Journal articleVieira de Castro G, Worm D, Grabe G, et al., 2022,
Characterisation of the key determinants of Phd antitoxin mediated Doc toxin inactivation in Salmonella
, ACS Chemical Biology, Vol: 17, Pages: 1598-1606, ISSN: 1554-8929In the search for novel antimicrobial therapeutics, toxin-antitoxin (TA) modules are promising yet underexplored targets for overcoming antibiotic failure. The bacterial toxin Doc has been associated with the persistence of Salmonella in macrophages, enabling its survival upon antibiotic exposure. After developing a novel method to produce the recombinant toxin, we have used antitoxin-mimicking peptides to thoroughly investigate the mechanism by which its cognate antitoxin Phd neutralizes the activity of Doc. We reveal insights into the molecular detail of the Phd–Doc relationship and discriminate antitoxin residues that stabilize the TA complex from those essential for inhibiting the activity of the toxin. Coexpression of Doc and antitoxin peptides in Salmonella was able to counteract the activity of the toxin, confirming our in vitro results with equivalent sequences. Our findings provide key principles for the development of chemical tools to study and therapeutically interrogate this important class of protein–protein interactions.
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Journal articleKahan R, Worm D, Vieira de Castro G, et al., 2021,
Modulators of protein–protein interactions as antimicrobial agents
, RSC Chemical Biology, Vol: 2, Pages: 387-409, ISSN: 2633-0679Protein–Protein interactions (PPIs) are involved in a myriad of cellular processes in all living organisms and the modulation of PPIs is already under investigation for the development of new drugs targeting cancers, autoimmune diseases and viruses. PPIs are also involved in the regulation of vital functions in bacteria and, therefore, targeting bacterial PPIs offers an attractive strategy for the development of antibiotics with novel modes of action. The latter are urgently needed to tackle multidrug-resistant and multidrug-tolerant bacteria. In this review, we describe recent developments in the modulation of PPIs in pathogenic bacteria for antibiotic development, including advanced small molecule and peptide inhibitors acting on bacterial PPIs involved in division, replication and transcription, outer membrane protein biogenesis, with an additional focus on toxin–antitoxin systems as upcoming drug targets.
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Journal articleRueda-Zubiaurre A, Yahiya S, Fischer O, et al., 2020,
Structure-activity relationship studies of a novel class of transmission blocking antimalarials targeting male gametes.
, Journal of Medicinal Chemistry, Vol: 63, Pages: 2240-2262, ISSN: 0022-2623Malaria is still a leading cause of mortality among children in the developing world, and despite the immense progress made in reducing the global burden, further efforts are needed if eradication is to be achieved. In this context, targeting transmission is widely recognized as a necessary intervention towards that goal. After carrying out a screen to discover new transmission-blocking agents, herein we report our medicinal chemistry efforts to study the potential of the most robust hit, DDD01035881, as a male-gamete targeted compound. We reveal key structural features for the activity of this series and identify analogues with greater potency and improved metabolic stability. We believe this study lays the groundwork for further development of this series as a transmission blocking agent.
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Journal articleFlack T, Romain C, White A, et al., 2019,
Design, synthesis and conformational analysis of oligobenzanilides as multi-facial alpha-helix mimetics
, Organic Letters, Vol: 21, Pages: 4433-4438, ISSN: 1523-7052The design, synthesis, and conformationalanalysis of an oligobenzanilide helix mimetic scaffold capableof simultaneous mimicry of two faces of an α-helix is reported.The synthetic methodology provides access to diversemonomer building blocks amenable to solid-phase assemblyin just four synthetic steps. The conformational flexibility ofmodel dimers was investigated using a combination of solidand solution state methodologies supplemented with DFTcalculations. The lack of noncovalent constraints allows forsignificant conformational plasticity in the scaffold, thuspermitting it to successfully mimic residues i, i+2, i+4, i+6, i+7, and i+9 of a canonical α-helix.
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Journal articleDelves M, Miguel-Blanco C, Matthews H, et al., 2018,
A high throughput screen for next-generation leads targeting malaria parasite transmission
, Nature Communications, Vol: 9, ISSN: 2041-1723Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2–1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male–female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population.
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Contact
Dr Anna Barnard
Wellcome Trust Sir Henry Dale Fellow
Department of Chemistry
Imperial College London
Wood Lane
London W12 0BZ
a.barnard@imperial.ac.uk
Tel: +44 (0)20 7594 8551