Loading...
5 results
Search Results
Now showing 1 - 5 of 5
- 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.
- 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.
- Cross-scale adaptive behaviors during the Upper Paleolithic in Iberia: The example of Vale Boi (Southwestern Portugal)Publication . Cascalheira, João; Bicho, Nuno; Manne, Tiina; Horta, PedroIt is now rather evident that, concomitant with the advent, growth and disappearance of the traditionally defined Western European Upper Paleolithic techno-complexes, a series of discrete eco-cultural niches would have existed within Iberia. Vale Boi, and its surroundings, may represent one of these niches, since its lengthy and fairly complete archaeological record clearly attests that the region was an attractive location for hunter-gatherer communities for over 10,000 years. From the first Modern Human occupations, c. 32 ka cal BP ago, a set of very specific cultural adaptive markers seem to have been developed in response to the particularities of the regional ecological background. Some of these strategies, such as intensive subsistence practices, raw-material specialized use, among others, were resilient through time and apparently impermeable to the major shifts in the techno-typological novelties brought about with the advent of each Upper Paleolithic phase. Even with the appearance of quite unique and broad-scale technologies, e. g. Solutrean, regional markers and identity have been kept, clearly showing that each level of the adaptive system seem to have operate at its own pace. This paper focus on long-term adaptive choices and on how and why hunter-gatherers inhabiting Vale Boi manage to absorb change and re-organize their system under new techno-complex cultural patterns while still retaining, efficiently, the same regional adaptive idiosyncrasies. Within the theoretical framework of Panarchy and the cross-scale resilience model we argue that cross-scale interactions between creative and conserving niche-specific behavioral adaptations were the keystone for the sustainability of hunter-gatherer cultural systems across the Late Pleistocene. c (C) 2017 Elsevier Ltd and INQUA. All rights reserved.
- Lithic bipolar methods as an adaptive strategy through space and timePublication . Horta, Pedro; Bicho, Nuno; Cascalheira, JoãoThe use of bipolar (on anvil) methods for resource exploitation has been identified in the archaeological record from the late Pliocene through to the Holocene. During all phases of human evolution, bipolar knapping and wedging were applied by different hominin species in a wide range of ecological settings. Studies on lithic bipolar methods have mainly focused on understanding the functional aspects of this technology. This paper explores the variability of the application of these methods during the Paleolithic on a macro scale. Through the meta-analysis of published data from 167 sites, it is posited that the use of bipolar methods may have had a significant impact on hominin expansion, adaptation, and survival strategies. Furthermore, the recurrent use of bipolar methods is not only an indicator of its success as an adaptive strategy, but also of how hominins were able to evaluate different types of efficiency through time.
- Curated character of the initial upper palaeolithic lithic artefact assemblages in Bacho Kiro Cave (Bulgaria)Publication . Tsanova, Tsenka; Delvigne, Vincent; Sirakova, Svoboda; Anastasova, Elka; Krumov, Ivaylo; Horta, Pedro; Marreiros, João; Nacheva, Elena; Rezek, Zeljko; Hublin, Jean-Jacques; Sirakov, Nikolay; Michael D. PetragliaThe dispersal of Homo sapiens across Eurasia during MIS 3 in the Late Pleistocene is marked by technological shifts and other behavioral changes, known in the archaeological record under the term of Initial Upper Paleolithic (IUP). Bacho Kiro Cave in north Bulgaria, re-excavated by us from 2015 to 2021, is one of the reference sites for this phenomenon. The newly excavated lithic assemblages dated by radiocarbon between 45,040 and 43,280 cal BP and attributed to Homo sapiens encompass more than two thousand lithic artifacts. The lithics, primarily from Layer N1-I, exist amid diverse fauna remains, human fossils, pierced animal teeth pendants, and sediment with high organic content. This article focuses on the technological aspects of the IUP lithics, covering raw material origin and use-life, blank production, on-site knapping activities, re-flaking of lithic implements, and the state of retouched lithic components. We apply petrography for the identification of silicites and other used stones. We employ cha & icirc;ne op & eacute;ratoire and reduction sequence approaches to profile the lithics techno-typologically and explore the lithic economy, particularly blade production methods, knapping techniques, and artifact curation. Raw material analysis reveals Lower Cretaceous flints from Ludogorie and Upper Cretaceous flints from the Danube region, up to 190 km and 130 km, respectively, from Bacho Kiro Cave, indicating long-distance mobility and finished products transport. Imported lithic implements, were a result of unidirectional and bidirectional non-Levallois laminar technology, likely of volumetric concept. Systematic on-anvil techniques (bipolar knapping) and tool segmentation indicate re-flaking and reshaping of lithic implements, reflecting on-site curation and multifaceted lithic economy. A limited comparison with other IUP sites reveals certain shared features and also regional variations. Bacho Kiro Cave significantly contributes to understanding the technological and behavioral evolution of early Homo sapiens in western Eurasia.