Percorrer por autor "O'Neill, Paul M."
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- Antimalarial agents as therapeutic tools against toxoplasmosis: a short bridge between two distant illnessesPublication . Secrieru, Alina; Costa, Inês C. C.; O'Neill, Paul M.; Cristiano, Maria De LurdesToxoplasmosis is an infectious disease with paramount impact worldwide, affecting many vulnerable populations and representing a significant matter of concern. Current therapies used against toxoplasmosis are based essentially on old chemotypes, which fail in providing a definitive cure for the disease, placing the most sensitive populations at risk for irreversible damage in vital organs, culminating in death in the most serious cases. Antimalarial drugs have been shown to possess key features for drug repurposing, finding application in the treatment of other parasite-borne illnesses, including toxoplasmosis. Antimalarials provide the most effective therapeutic solutions against toxoplasmosis and make up for the majority of currently available antitoxoplasmic drugs. Additionally, other antiplasmodial drugs have been scrutinized and many promising candidates have emanated in recent developments. Available data demonstrate that it is worthwhile to explore the activity of classical and most recent antimalarial chemotypes, such as quinolines, endoperoxides, pyrazolo[1,5-a]pyrimidines, and nature-derived peptide-based parasiticidal agents, in the context of toxoplasmosis chemotherapy, in the quest for encountering more effective and safer tools for toxoplasmosis control or eradication.
- Artemisinin inspired synthetic endoperoxide drug candidates: Design, synthesis, and mechanism of action studiesPublication . Woodley, Christopher M.; Amado, Patrícia; Cristiano, Maria De Lurdes; O'Neill, Paul M.Artemisinin combination therapies (ACTs) have been used as the first-line treatments against Plasmodium falciparum malaria for decades. Recent advances in chemical proteomics have shed light on the complex mechanism of action of semi-synthetic artemisinin (ARTs), particularly their promiscuous alkylation of parasite proteins via previous heme-mediated bioactivation of the endoperoxide bond. Alarmingly, the rise of resistance to ART in South East Asia and the synthetic limitations of the ART scaffold have pushed the course for the necessity of fully synthetic endoperoxide-based antimalarials. Several classes of synthetic endoperoxide antimalarials have been described in literature utilizing various endoperoxide warheads including 1,2-dioxanes, 1,2,4-trioxanes, 1,2,4-trioxolanes, and 1,2,4,5-tetraoxanes. Two of these classes, the 1,2,4-trioxolanes (arterolane and artefenomel) and the 1,2,4,5-tetraoxanes (N205 and E209) based antimalarials, have been explored extensively and are still in active development. In contrast, the most recent publication pertaining to the development of the 1,2-dioxane, Arteflene, and 1,2,4-trioxanes fenozan-50F, DU1301, and PA1103/SAR116242 was published in 2008. This review summarizes the synthesis, biological and clinical evaluation, and mechanistic studies of the most developed synthetic endoperoxide antimalarials, providing an update on those classes still in active development.
- Artemisinin-polypyrrole conjugates: synthesis, DNA binding studies and preliminary antiproliferative evaluationPublication . La Pensée, Louise; Sabbani, Sunil; Sharma, Raman; Bhamra, Inder; Shore, Emma; Chadwick, Amy E.; Berry, Neil; Firman, J.; Araujo, Nuna C. P.; Cabral, Lília; Cristiano, Maria Lurdes Santos; Bateman, Cerys; Janneh, Omar; Gavrila, Adelina; Wu, Yi Hang; Hussain, Afthab; Ward, Stephen A.; Stocks, Paul A.; Cosstick, Rick; O'Neill, Paul M.Artemisinin-based combination therapies (ACTs) are currently the recommended treatment for uncomplicated and severe cases of malaria.[1] Additionally, artemisinins, as well as a number of other sesquiterpene lactones (SLs), are currently in phase I–II clinical trials against breast, colorectal and nonsmall-cell lung cancers.[2] As outlined by the iron-dependent activation hypothesis,[3] the activity of artemisinin (ART) is dependent on the endoperoxide bridge.[4] The peroxide is cleaved by endogenous sources of FeII to generate highly reactive carbon-centred radicals (CCRs), which are believed to react with critical cellular targets.[3] ART demonstrates selectivity towards rapidly proliferating cancer cell lines that possess a high intracellular iron content required to sustain their characteristic high rates of multiplication.[5] Iron activation links this particular potency of ART towards rapidly proliferating cancer cell lines; differentiation between healthy and cancerous cells by variation of iron concentration provides a strategy for selective cytotoxicity by ART and its derivatives.[4] The mechanism by which ART exerts its cytotoxic activity still remains elusive. ART acts by disruption of proliferation,[6, 7] oxidative stress,[8] anti-angiogenesis,[9] NF-kB signalling,[10] apoptosis[4] and interfering with iron uptake and metabolism.[6] ART also induces DNA breakage,[11] and it has been reported that artesunate-mediated DNA damage contributes to its therapeutic efficacy.
- Design and synthesis of novel 2-pyridone peptidomimetic falcipain 2/3 inhibitorsPublication . Verissimo, Edite; Berry, Neil; Gibbons, Peter D.; Cristiano, Maria Lurdes Santos; Rosenthal, Philip J.; Gut, Jiri; Ward, Stephen A.; O'Neill, Paul M.The structure-based design, chemical synthesis and in vitro activity evaluation of various falcipain inhibitors derived from 2-pyridone are reported. These compounds contain a peptidomimetic binding determinant and a Michael acceptor terminal moiety capable of deactivating the cysteine protease active site.
- Diels–alder/thiol–olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophorePublication . O'Neill, Paul M.; Verissimo, Edite; Ward, Stephen A.; Davies, Jill; Korshin, Edward E.; Araujo, Nuna C. P.; Pugh, Matthew D.; Cristiano, Maria Lurdes Santos; Stocks, Paul A.; Bachi, Mario D.Abstract—A Diels–Alder/thiol–olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a–22b is reported. Some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of the synthetic antimalarial agent arteflene. Iron(II)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with TEMPO provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. Reactive C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides.
- Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: toward combination chemotherapy of malaria through a single chemical entityPublication . Gibbons, Peter D.; Verissimo, Edite; Araujo, Nuna C. P.; Barton, Victoria; Nixon, Gemma L.; Amewu, Richard K.; Chadwick, J.; Stocks, Paul A.; Biagini, Giancarlo A.; Srivastava, Abhishek; Rosenthal, Philip J.; Gut, Jiri; Guedes, Rita C.; Moreira, Rui; Sharma, Raman; Berry, Neil; Cristiano, Maria Lurdes Santos; Shone, Alison E.; Ward, Stephen A.; O'Neill, Paul M.We extend our approach of combination chemotherapy through a single prodrug entity (O’Neill et al. Angew. Chem., Int. Ed. 2004, 43, 4193) by using a 1,2,4-trioxolane as a protease inhibitor carbonylmasking group. These molecules are designed to target the malaria parasite through two independent mechanisms of action: iron(II) decomposition releases the carbonyl protease inhibitor and potentially cytotoxic C-radical species in tandem. Using a proposed target “heme”, we also demonstrate heme alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized red blood cells.
- Examination of the cytotoxic and embryotoxic potential and underlying mechanisms of next-generation synthetic trioxolane and tetraoxane antimalarialsPublication . Copple, I. M.; Mercer, A. E.; Firman, J.; Donegan, G.; Herpers, B.; Wong, M. H.; Chadwick, J.; Bringela, A.; Cristiano, Maria Lurdes Santos; Van De Water, B.; Ward, Stephen A.; O'Neill, Paul M.; Park, B. K.Semisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria.
- On the ordeal of quinolone preparation via cyclisation of aryl-enamines; synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylatePublication . Horta, Pedro; Henriques, Marta S. C.; Bras, Elisa M.; Murtinheira, Fernanda; Nogueira, Fatima; O'Neill, Paul M.; Paixao, Jose A.; Fausto, Rui; Cristiano, Maria De LurdesRecent studies directed to the design of compounds targeting the bc(1) protein complex of Plasmodium falciparum, the parasite responsible for most lethal cases of malaria, identified quinolones (4-oxo-quinolines) with low nanomolar inhibitory activity against both the enzyme and infected erythrocytes. The 4-oxo-quinoline 3-ester chemotype emerged as a possible source of potent bc(1) inhibitors, prompting us to expand the library of available analogs for SAR studies and subsequent lead optimization. We now report the synthesis and structural characterization of unexpected ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)quinoline-3-carboxylate, a 4-aryloxy-quinoline 3-ester formed during attempted preparation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate (4-oxo-quinoline 3-ester). We propose that the 4-aryloxy-quinoline 3-ester derives from 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate (4-hydroxy-quinoline 3-ester), the enol form of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate. Formation of the 4-aryloxy-quinoline 3-ester confirms the impact of quinolone/hydroxyquinoline tautomerism, both on the efficiency of synthetic routes to quinolones and on pharmacologic profiles. Tautomers exhibit different cLogP values and interact differently with the enzyme active site. A structural investigation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate and 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, using matrix isolation coupled to FTIR spectroscopy and theoretical calculations, revealed that the lowest energy conformers of 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, lower in energy than their most stable 4-oxo-quinoline tautomer by about 27 kJ mol(-1), are solely present in the matrix, while the most stable 4-oxo-quinoline tautomer is solely present in the crystalline phase.
- Rational design, synthesis, and biological evaluation of heterocyclic quinolones targeting the respiratory chain of Mycobacterium tuberculosisPublication . Hong, W. David; Gibbons, Peter D.; Leung, Suet C.; Amewu, Richard; Stocks, Paul A.; Stachulski, Andrew; Horta, Pedro; Cristiano, Maria De Lurdes; Shone, Alison E.; Moss, Darren; Ardrey, Alison; Sharma, Raman; Warman, Ashley J.; Bedingfield, Paul T. P.; Fisher, Nicholas E.; Aljayyoussi, Ghaith; Mead, Sally; Caws, Maxine; Berry, Neil G.; Ward, Stephen A.; Biagini, Giancarlo A.; O'Neill, Paul M.; Nixon, Gemma L.A high-throughput screen (HTS) was undertaken against the respiratory chain dehydrogenase component, NADH:menaquinone oxidoreductase (Ndh) of Mycobacterium tuberculosis (Mtb). The 11000 compounds were selected for the HTS based on the known phenothiazine Ndh inhibitors, trifluoperazine and thioridazine. Combined HTS (11000 compounds) and in-house screening of a limited number of quinolones (50 compounds) identified similar to 100 hits and four distinct chemotypes, the most promising of which contained the quinolone core. Subsequent Mtb screening of the complete in-house quinolone library (350 compounds) identified a further similar to 90 hits across three quinolone subtemplates. Quinolones containing the amine-based side chain were selected as the pharmacophore for further modification, resulting in metabolically stable quinolones effective against multi drug resistant (MDR) Mtb. The lead compound, 42a (MTC420), displays acceptable antituberculosis activity (Mtb IC50 = 525 nM, Mtb Wayne IC50 = 76 nM, and MDR Mtb patient isolates IC50 = 140 nM) and favorable pharmacokinetic and toxicological profiles.
- Semi-synthetic and synthetic 1,2,4-trioxaquines and 1,2,4-trioxolaquines: synthesis, preliminary SAR and comparison with acridine endoperoxide conjugatesPublication . Araujo, Nuna C. P.; Barton, Victoria; Jones, Michael; Stocks, Paul A.; Ward, Stephen A.; Davies, Jill; Bray, Patrick G.; Shone, Alison E.; Cristiano, Maria Lurdes Santos; O'Neill, Paul M.A novel series of semi-synthetic trioxaquines and synthetic trioxolaquines were prepared, in moderate to good yields. Antimalarial activity was evaluated against both the chloroquine-sensitive 3D7 and resistant K1 strain of Plasmodium falciparum and both series of compounds were shown to be active in the low nanomolar range. For comparison the corresponding 9-amino acridine analogues were also prepared and shown to have low nanomolar activity like their quinoline counterparts.