Publications by authors named "Elisa Azzali"

9 Publications

  • Page 1 of 1

2-Aminooxazole as a Novel Privileged Scaffold in Antitubercular Medicinal Chemistry.

ACS Med Chem Lett 2020 Jul 8;11(7):1435-1441. Epub 2020 Jun 8.

P4T group and Food and Drug Department, University of Parma, 43124 Parma, Italy.

To obtain effective eradication of numerous infectious diseases such as tuberculosis, it is important to supply the medicinal chemistry arsenal with novel chemical agents. Isosterism and bioisosterism are widely known concepts in the field of early drug discovery, and in several cases, rational isosteric replacements have contributed to improved efficacy and physicochemical characteristics throughout the hit-to-lead optimization process. However, sometimes the synthesis of isosteres might not be as straightforward as that of the parent compounds, and therefore, novel synthetic strategies must be elaborated. In this regard, we herein report the evaluation of a series of N-substituted 4-phenyl-2-aminooxazoles that, despite being isosteres of a widely used nucleus such as the 2-aminothiazole, have been only seldom explored. After elaboration of a convenient synthetic strategy, a small set of 2-aminothiazoles and their 2-aminooxazole counterparts were compared with regard to antitubercular activity and physicochemical characteristics.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357219PMC
July 2020

Adjuvant therapies against tuberculosis: discovery of a 2-aminothiazole targeting Mycobacterium tuberculosis energetics.

Future Microbiol 2018 09 27;13:1383-1402. Epub 2018 Sep 27.

Global Health & Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Lisboa, Portugal.

Aim: To evaluate the activity of the 2-aminothiazole UPAR-174 following an unexplored approach: targeting Mycobacterium tuberculosis with lipophilic compounds that present antituberculosis and efflux inhibitory activity.

Methods: Antituberculosis activity was assessed against replicating, nonreplicating and intracellular bacilli. Its capacity to inhibit active efflux was determined. ATP quantification and membrane potential analysis were performed. Intracellular activity was studied on human-monocyte-derived macrophages.

Results: UPAR-174 is an efflux inhibitor active against replicating, nonreplicating and intracellular M. tuberculosis. It dissipates the membrane potential and causes ATP depletion.

Conclusion: Targeting M. tuberculosis with lipophilic efflux inhibitors, exploring their dual activity - dissipation of the proton motive force and efflux inhibition - represents an attractive strategy to fight against drug-resistant tuberculosis.
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http://dx.doi.org/10.2217/fmb-2018-0110DOI Listing
September 2018

Modulation of bacterial metabolism by the microenvironment controls MAIT cell stimulation.

Mucosal Immunol 2018 07 9;11(4):1060-1070. Epub 2018 May 9.

Experimental Immunology, Department of Biomedicine, University and University Hospital Basel, 4031, Basel, Switzerland.

Mucosal-associated invariant T (MAIT) cells are abundant innate-like T lymphocytes in mucosal tissues and recognize a variety of riboflavin-related metabolites produced by the microbial flora. Relevant issues are whether MAIT cells are heterogeneous in the colon, and whether the local environment influences microbial metabolism thereby shaping MAIT cell phenotypes and responses. We found discrete MAIT cell populations in human colon, characterized by the diverse expression of transcription factors, cytokines and surface markers, indicative of activated and precisely controlled lymphocyte populations. Similar phenotypes were rare among circulating MAIT cells and appeared when circulating MAIT cells were stimulated with the synthetic antigens 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil, and 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil. Furthermore, bacteria grown in colon-resembling conditions with low oxygen tension and harvested at stationary growth phase, potently activated human MAIT cells. The increased activation correlated with accumulation of the above antigenic metabolites as indicated by mass spectrometry. Thus, the colon environment contributes to mucosal immunity by directly affecting bacterial metabolism, and indirectly controlling the stimulation and differentiation of MAIT cells.
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http://dx.doi.org/10.1038/s41385-018-0020-9DOI Listing
July 2018

Substituted N-Phenyl-5-(2-(phenylamino)thiazol-4-yl)isoxazole-3-carboxamides Are Valuable Antitubercular Candidates that Evade Innate Efflux Machinery.

J Med Chem 2017 08 10;60(16):7108-7122. Epub 2017 Aug 10.

Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL , Rua da Junqueira, 100, 1349-008 Lisbon, Portugal.

Tuberculosis remains one of the deadliest infectious diseases in the world, and the increased number of multidrug-resistant and extremely drug-resistant strains is a significant reason for concern. This makes the discovery of novel antitubercular agents a cogent priority. We have previously addressed this need by reporting a series of substituted 2-aminothiazoles capable to inhibit the growth of actively replicating, nonreplicating persistent, and resistant Mycobacterium tuberculosis strains. Clues from the structure-activity relationships lining up the antitubercular activity were exploited for the rational design of improved analogues. Two compounds, namely N-phenyl-5-(2-(p-tolylamino)thiazol-4-yl)isoxazole-3-carboxamide 7a and N-(pyridin-2-yl)-5-(2-(p-tolylamino)thiazol-4-yl)isoxazole-3-carboxamide 8a, were found to show high inhibitory activity toward susceptible M. tuberculosis strains, with an MIC of 0.125-0.25 μg/mL (0.33-0.66 μM) and 0.06-0.125 μg/mL (0.16-0.32 μM), respectively. Moreover, they maintained good activity also toward resistant strains, and they were selective over other bacterial species and eukaryotic cells, metabolically stable, and apparently not susceptible to the action of efflux pumps.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00793DOI Listing
August 2017

Accepting the Invitation to Open Innovation in Malaria Drug Discovery: Synthesis, Biological Evaluation, and Investigation on the Structure-Activity Relationships of Benzo[b]thiophene-2-carboxamides as Antimalarial Agents.

J Med Chem 2017 03 14;60(5):1959-1970. Epub 2017 Feb 14.

Centro Interdipartimentale Misure (CIM) 'G. Casnati', University of Parma , Parco Area delle Scienze 23/A, 43124 Parma, Italy.

Malaria eradication is a global health priority, but current therapies are not always suitable for providing a radical cure. Artemisinin has paved the way for the current malaria treatment, the so-called Artemisinin-based Combination Therapy (ACT). However, with the detection of resistance to ACT, innovative compounds active against multiple parasite species and at multiple life stages are needed. GlaxoSmithKline has recently disclosed the results of a phenotypic screening of an internal library, publishing a collection of 400 antimalarial chemotypes, termed the "Malaria Box". After analysis of the data set, we have carried out a medicinal chemistry campaign in order to define the structure-activity relationships for one of the released compounds, which embodies a benzothiophene-2-carboxamide core. Thirty-five compounds were prepared, and a description of the structural features responsible for the in vitro activity against different strains of P. falciparum, the toxicity, and the metabolic stability is herein reported.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01685DOI Listing
March 2017

An Experimental Model for the Rapid Screening of Compounds with Potential Use Against Mycobacteria.

Assay Drug Dev Technol 2016 11;14(9):524-534

1 Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa , UNL, Lisbon, Portugal .

Infections caused by Mycobacterium tuberculosis and other mycobacteria are major challenges for global public health. Particularly worrisome are infections caused by multidrug-resistant bacteria, which are increasingly difficult to treat because of the loss of efficacy of the current antibacterial agents, a problem that continues to escalate worldwide. There has been a limited interest and investment on the development of new antibacterial agents in the past decades. This has led to the current situation, in which there is an urgent demand for innovative therapeutic alternatives to fight infections caused by multidrug-resistant pathogens, such as multidrug-resistant tuberculosis. The identification of compounds that can act as adjuvants in antimycobacterial therapeutic regimens is an appealing strategy to restore the efficacy lost by some of the antibiotics currently used and shorten the duration of the therapeutic regimen. In this work, by setting Mycobacterium smegmatis as a model organism, we have developed a methodological strategy to identify, in a fast and simple approach, compounds with antimycobacterial activity or with potential adjuvant properties, by either inhibition of efflux or other unrelated mechanisms. Such an approach may increase the rate of identification of promising molecules, to be further explored in pathogenic models for their potential use either as antimicrobials or as adjuvants, in combination with available therapeutic regimens for the treatment of mycobacterial infections. This method allowed us to identify a new molecule that shows promising activity as an efflux inhibitor in M. smegmatis.
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http://dx.doi.org/10.1089/adt.2016.752DOI Listing
November 2016

A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin.

Bioorg Med Chem 2016 07 24;24(14):3174-83. Epub 2016 May 24.

Center for Multidisciplinary Research, Institute of Nuclear Sciences Vinca, University of Belgrade, POB 522, Mihaila Petrovica Alasa 14, 11001 Belgrade, Serbia. Electronic address:

The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I1-type imidazoline receptors (I1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from α2-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine-derived compounds with anticancer potential and devoid of α2-adrenoceptor effects by means of ligand- and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to α2-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers.
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http://dx.doi.org/10.1016/j.bmc.2016.05.043DOI Listing
July 2016

Rational Design and Synthesis of Thioridazine Analogues as Enhancers of the Antituberculosis Therapy.

J Med Chem 2015 Aug 3;58(15):5842-53. Epub 2015 Aug 3.

‡Grupo de Micobactérias, Unidade de Microbiologia Médica, Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT, UNL), Rua da Junqueira, 100, 1349-008 Lisbon, Portugal.

Tuberculosis, caused by Mycobacterium tuberculosis, is still one of the leading infectious diseases globally. Therefore, novel approaches are needed to face this disease. Efflux pumps are known to contribute to the emergence of M. tuberculosis drug resistance. Thioridazine has shown good anti-TB properties both in vitro and in vivo, likely due to its capacity to inhibit efflux mechanisms. Here we report the design and synthesis of a number of putative efflux inhibitors inspired by the structure of thioridazine. Compounds were evaluated for their in vitro and ex vivo activity against M. tuberculosis H37Rv. Compared to the parent molecule, some of the compounds synthesized showed higher efflux inhibitory capacity, less cytotoxicity, and a remarkable synergistic effect with anti-TB drugs both in vitro and in human macrophages, demonstrating their potential to be used as coadjuvants for the treatment of tuberculosis.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00428DOI Listing
August 2015

Further insights into the SAR of α-substituted cyclopropylamine derivatives as inhibitors of histone demethylase KDM1A.

Eur J Med Chem 2015 Mar 7;92:377-86. Epub 2015 Jan 7.

Dipartimento Farmaceutico, University of Parma, Parco Area delle Scienze 27/A, Parma 43124, Italy. Electronic address:

Epigenetics alterations including histone methylation and acetylation, and DNA methylation, are thought to play important roles in the onset and progression of cancer in numerous tumour cell lines. Lysine-specific demethylase 1 (LSD1 or KDM1A) is highly expressed in different cancer types and inhibiting KDM1A activity seems to have high therapeutic potential in cancer treatment. In the recent years, several inhibitors of KDM1A have been prepared and disclosed. The majority of these derivatives were designed based on the structure of tranylcypromine, as the cyclopropane core is responsible for the covalent interaction between the inhibitor and the catalytic domain of KDM proteins. In this study, we have further extended the SAR regarding compounds 1a-e, which were recently found to inhibit KDM1A with good activity. The decoration of the phenyl ring at the β-position of the cyclopropane ring with small functional groups, mostly halogenated, and in particular at the meta position, led to a significant improvement of the inhibitory activity against KDM1A, as exemplified by compound 44a, which has a potency in the low nanomolar range (31 nM).
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http://dx.doi.org/10.1016/j.ejmech.2014.12.032DOI Listing
March 2015