Publications by authors named "Alessandro De Logu"

34 Publications

6-Fluorophenylbenzohydrazides inhibit Mycobacterium tuberculosis growth through alteration of tryptophan biosynthesis.

Eur J Med Chem 2021 Sep 9;226:113843. Epub 2021 Sep 9.

Department of Chemistry and Technologies of Drug, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Rome, Italy. Electronic address:

A major constraint in reducing tuberculosis epidemic is the emergence of strains resistant to one or more of clinically approved antibiotics, which emphasizes the need of novel drugs with novel targets. Genetic knockout strains of Mycobacterium tuberculosis (Mtb) have established that tryptophan (Trp) biosynthesis is essential for the bacterium to survive in vivo and cause disease in animal models. An anthranilate-like compound, 6-FABA, was previously shown to synergize with the host immune response to Mtb infection in vivo. Herein, we present a class of anthranilate-like compounds endowed with good antimycobacterial activity and low cytotoxicity. We show how replacing the carboxylic moiety with a hydrazide led to a significant improvement in both activity and cytotoxicity relative to the parent compound 6-FABA. Several new benzohydrazides (compounds 20-31, 33, 34, 36, 38 and 39) showed good activities against Mtb (0.625 ≤ MIC≤6.25 μM) and demonstrated no detectable cytotoxicity against Vero cell assay (CC ≥ 1360 μM). The target preliminary studies confirmed the hypothesis that this new class of compounds inhibits Trp biosynthesis. Taken together, these findings indicate that fluorophenylbenzohydrazides represent good candidates to be assessed for drug discovery.
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http://dx.doi.org/10.1016/j.ejmech.2021.113843DOI Listing
September 2021

Novel Pyrazole-Containing Compounds Active against .

ACS Med Chem Lett 2019 Oct 18;10(10):1423-1429. Epub 2019 Sep 18.

Department of Chemistry and Technologies of Drug, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy.

In this study, a series of 49 five-membered heterocyclic compounds containing either a pyridine- or a pyrrole-type nitrogen were synthesized and tested against . Among them, only the 1,3,5-trisubstituted pyrazoles - exhibited minimum inhibitory concentration values in the low micromolar range, and some also exhibited an improved physicochemical profile without cytotoxic effects. Three pyrazoles were subjected to an animal tuberculosis efficacy model, and compound induced a statistically significant difference in lung bacterial counts compared with untreated mice. Moreover, to determine the target of this series, resistors were generated, and whole genome sequencing revealed mutations in the gene.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792160PMC
October 2019

Design, synthesis and antimycobacterial activity of benzoxazinone derivatives and open-ring analogues: Preliminary data and computational analysis.

Bioorg Med Chem Lett 2019 09 17;29(17):2468-2474. Epub 2019 Jul 17.

Pharmacy and Clinical Pharmacology Department, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Via dell'Istria 65/1, 34137 Trieste, Italy.

This study examines in depth benzoxazine nucleus for antimycobacterial property. We synthesized some benzoxazin-2-one and benzoxazin-3-one derivatives, which were tested for activity against a panel of Mycobacterium tuberculosis (Mtb) strains, including H37Ra, H37Rv and some resistant strains. Several compounds displayed a high antimycobacterial activity and the three isoniazid analogue derivatives 8a-c exhibited a MIC range of 0.125-0.250 μg/mL (0.37-0.75 μM) against strain H37Ra, therefore lower than the isoniazid reference drug. Two benzoxazin-2-one derivatives, 1c and 5j, together with isoniazid-analogue compound 8a, also revealed low MIC values against resistant strains and proved highly selective for mycobacterial cells, compared to mammalian Vero cells. To predict whether molecule 8a is able to interact with the active site of InhA, we docked it into the crystal structure; indeed, during the molecular dynamic simulation the compound never left the protein pocket. The more active compounds were predicted for ADME properties and all proved to be potentially orally active in humans.
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http://dx.doi.org/10.1016/j.bmcl.2019.07.025DOI Listing
September 2019

Imidazole and 1,2,4-Triazole-based Derivatives Gifted with Antitubercular Activity: Cytotoxicity and Computational Assessment.

Curr Top Med Chem 2019 ;19(8):620-632

Department of Chemistry and Pharmaceutical Sciences, P.le Europa 1, University of Trieste, 34127 Trieste, Italy.

Background: Mycobacterium Tuberculosis (Mtb) is the causative pathogen of Tuberculosis (TB) and outbreaks are more common among immunosuppressed persons infected with HIV. The current treatment regimens are lengthy and toxic, yet the therapy has remained unchanged for many decades, so there is a need to find new structures with selective mechanism of action. Moreover, the increased incidence of severe disseminated infections produced by undiagnosed Multidrug-resistant (MDR), worsen clinical treatment and contribute the spread of the disease.

Objective: The aim of our study was to evaluate the potential of imidazole and triazole moieties for antimycobacterial activity, by synthesizing some 1-(1-(aryl)-2-(2,6-dichlorophenyl)hydrazono)ethyl- 1H-imidazole and 1H-1,2,4-triazole derivatives 2a-l.

Methods: The title compounds were obtained via classical organic synthesis. The antimicrobial activity was evaluated using the method of microdilution and the cytotoxicity assay was performed by MTT method.

Results: The results indicated that the presence of both the imidazole ring and that of the 2,6- dichlorosubstituted phenyl moiety, is more relevant for inhibitory activity against Mtb than the triazole nucleus and the unsubstituted phenyl ring. Among the series, (E)-1-(2-(5-chlorothiophen-2-yl)-2-(2- (2,6-dichlorophenyl)hydrazono)ethyl)-1H-imidazole derivative 2f and (Z)-1-(2-([1,1'-biphenyl]-4-yl)- 2-(2-(2,6-dichlorophenyl)hydrazono)ethyl]-1H-imidazole derivatives 2e exhibited a promising antimycobacterial property and the latter also displayed a safe cytotoxic profile.

Conclusion: The synthesized compounds were studied for their antitubercular activity. Among the series, the compounds 2e and 2f appeared to be the most promising agents and, according to the docking assessment, the compounds could be CYP51 inhibitors. These evidences could be useful for the future development of new antimycobacterial derivatives targeting CYP51 with more specificity for the mycobacterial cell enzyme.
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http://dx.doi.org/10.2174/1568026619666190227183826DOI Listing
July 2019

Design, synthesis, SAR and biological investigation of 3-(carboxymethyl)rhodanine and aminothiazole inhibitors of Mycobacterium tuberculosis Zmp1.

Bioorg Med Chem Lett 2018 02 31;28(4):637-641. Epub 2018 Jan 31.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53019 Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Bldg., Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA. Electronic address:

Sixteen 3-(carboxymethyl)rhodanines, and twelve aminothiazoles as rhodanine-mimetics were designed, synthesized and tested as inhibitors of the Zmp1 enzyme from Mycobacterium tuberculosis (Mtb). Almost all rhodanines (5a-d, 5f-n, and 7a-b) exhibited Zmp1 inhibition with IC values in the range 1.3-43.9 µM, whereas only aminothiazoles 12b and 12d proved active with IC values of 41.3 and 35.7 µM, respectively. Structure-activity relationships (SAR) were coupled with molecular modeling studies to highlight structural determinants for Zmp1 inhibition. Moreover, rhodanines 5a and 5c induced 23.4 and 53.8% of Mtb growth inhibition in THP-1 infected cells, respectively, at the non-toxic concentration of 10 µg/ml. This work represents a step forward in targeting Zmp1 by small molecules.
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http://dx.doi.org/10.1016/j.bmcl.2018.01.031DOI Listing
February 2018

In vivo potent BM635 analogue with improved drug-like properties.

Eur J Med Chem 2018 Feb 27;145:539-550. Epub 2017 Dec 27.

Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy. Electronic address:

BM635 is the hit compound of a promising anti-TB compound class. Herein we report systematic variations around the central pyrrole core of BM635 and we describe the design, synthesis, biological evaluation, pharmacokinetic analysis, as well as in vivo TB mouse efficacy studies of novel BM635 analogues that show improved physicochemical properties. This hit-to-lead campaign led to the identification of a new analogue, 4-((1-isopropyl-5-(4-isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)morpholine (17), that shows excellent activity (MIC = 0.15 μM; SI = 133) against drug-sensitive Mycobacterium tuberculosis strains, as well as efficacy in a murine model of TB infection.
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http://dx.doi.org/10.1016/j.ejmech.2017.12.075DOI Listing
February 2018

Naturally occurring Diels-Alder-type adducts from Morus nigra as potent inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B.

Eur J Med Chem 2018 Jan 7;144:277-288. Epub 2017 Dec 7.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy; Center for Life Nano [email protected], Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161, Roma, Italy. Electronic address:

Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatases A and B (PtpA and PtpB) have been recognized as potential molecular targets for the development of new therapeutic strategies against tuberculosis (TB). In this context, we have recently reported that the naturally occurring Diels-Alder-type adduct Kuwanol E is an inhibitor of PtpB (K = 1.6 ± 0.1 μM). Here, we describe additional Diels-Alder-type adducts isolated from Morus nigra roots bark that inhibit PtpB at sub-micromolar concentrations. The two most potent compounds, namely Kuwanon G and Kuwanon H, showed K values of 0.39 ± 0.27 and 0.20 ± 0.01 μM, respectively, and interacted with the active site of the enzyme as suggested by kinetics and mass spectrometry studies. Molecular docking coupled with intrinsic fluorescence analysis and isothermal titration calorimetry (ITC) further characterized the interaction of these promising PtpB inhibitors. Notably, in an Mtb survival assay inside macrophages, Kuwanon G showed inhibition of Mtb growth by 61.3%. All these results point to the common Diels-Alder-type adduct scaffold, and highlight its relevance for the development of PtpB inhibitors as candidate therapeutics for TB.
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http://dx.doi.org/10.1016/j.ejmech.2017.11.087DOI Listing
January 2018

Antimycobacterial activity of new N(1)-[1-[1-aryl-3-[4-(1H-imidazol-1-yl)phenyl]-3-oxo]propyl]-pyridine-2-carboxamidrazone derivatives.

Bioorg Med Chem Lett 2016 07 19;26(14):3287-3290. Epub 2016 May 19.

Department of Life and Enviromental Sciences, Via Porcell 4, University of Cagliari, 09124 Cagliari, Italy.

N(1)-[1-[1-aryl-3-[4-(1H-imidazol-1-yl)phenyl]-3-oxo]propyl]-pyridine-2-carboxamidrazone derivatives were design, synthesized and tested for their in vitro antimycobacterial activity. The new compounds showed a moderate antimycobacterial activity against the tested strain of Mycobacterium tuberculosis H37Ra and a significant antimycobacterial activity against several mycobacteria other than tuberculosis strains.
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http://dx.doi.org/10.1016/j.bmcl.2016.05.053DOI Listing
July 2016

Discovery of in vitro antitubercular agents through in silico ligand-based approaches.

Eur J Med Chem 2016 Oct 20;121:169-180. Epub 2016 May 20.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53019 Siena, Italy; Sbarro Institute for Cancer Research & Molecular Medicine, Center for Biotechnology, College of Science & Technology, Temple University, BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA. Electronic address:

The development of new anti-tubercular agents represents a constant challenge mostly due to the insurgency of resistance to the currently available drugs. In this study, a set of 60 molecules were selected by screening the Asinex and the ZINC collections and an in house library by means of in silico ligand-based approaches. Biological assays in Mycobacterium tuberculosis H37Ra ATCC 25177 strain highlighted (±)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethyl-4-(3,4-dichlorophenyl)piperazine-1-carboxylate (5i) and 3-(4-chlorophenyl)-5-(2,4-dimethylpyrimidin-5-yl)-2-methylpyrazolo[1.5-a]pyrimidin-7(4H)-one (42) as the most potent compounds, having a Minimum Inhibitory Concentration (MIC) of 4 and 2 μg/mL respectively. These molecules represent a good starting point for further optimization of effective anti-TB agents.
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http://dx.doi.org/10.1016/j.ejmech.2016.05.032DOI Listing
October 2016

Exploring the thiazole scaffold for the identification of new agents for the treatment of fluconazole resistant Candida.

J Enzyme Inhib Med Chem 2016 Dec 8;31(6):1672-7. Epub 2016 Jan 8.

a Department of Life and Environmental Sciences , University of Cagliari , Cagliari , Italy .

Cyclohexyliden- and 2-methylcyclohexyliden-hydrazo-4-arylthiazoles were synthesized and tested as antifungal agents. All compounds exhibited minimal inhibitory concentration (MIC) values comparable with those of fluconazole (FLC). Moreover, some compounds showed fungicidal activity at low concentration. Worth noting five out of nine compounds were active towards Candida albicans 25 FLC resistant isolated from clinical specimens. The cellular toxicity was evaluated and none of the compounds is toxic at the MIC. On the basis of our data we can conclude that these derivatives are promising agents for the treatment of resistant C. albicans.
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http://dx.doi.org/10.3109/14756366.2015.1113171DOI Listing
December 2016

Limonoids from Melia azedarach Fruits as Inhibitors of Flaviviruses and Mycobacterium tubercolosis.

PLoS One 2015 20;10(10):e0141272. Epub 2015 Oct 20.

Department of Life and Environmental Sciences, High Resolution Mass Spectrometry Laboratory, University of Cagliari, Italy.

The biological diversity of nature is the source of a wide range of bioactive molecules. The natural products, either as pure compounds or as standardized plant extracts, have been a successful source of inspiration for the development of new drugs. The present work was carried out to investigate the cytotoxicity, antiviral and antimycobacterial activity of the methanol extract and of four identified limonoids from the fruits of Melia azedarach (Meliaceae). The extract and purified limonoids were tested in cell-based assays for antiviral activity against representatives of ssRNA, dsRNA and dsDNA viruses and against Mycobacterium tuberculosis. Very interestingly, 3-α-tigloyl-melianol and melianone showed a potent antiviral activity (EC50 in the range of 3-11μM) against three important human pathogens, belonging to Flaviviridae family, West Nile virus, Dengue virus and Yellow Fever virus. Mode of action studies demonstrated that title compounds were inhibitors of West Nile virus only when added during the infection, acting as inhibitors of the entry or of a very early event of life cycle. Furthermore, 3-α-tigloyl-melianol and methyl kulonate showed interesting antimycobacterial activity (with MIC values of 29 and 70 μM respectively). The limonoids are typically lipophilic compounds present in the fruits of Melia azeradach. They are known as cytotoxic compounds against different cancer cell lines, while their potential as antiviral and antibacterial was poorly investigated. Our studies show that they may serve as a good starting point for the development of novel drugs for the treatment of infections by Flaviviruses and Mycobacterium tuberculosis, for which there is a continued need.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141272PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612778PMC
June 2016

Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute murine model of tuberculosis infection.

PLoS One 2013 21;8(2):e56980. Epub 2013 Feb 21.

Istituto Pasteur Fondazione Cenci-Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Roma, Italy.

1,5-Diphenyl pyrroles were previously identified as a class of compounds endowed with high in vitro efficacy against M. tuberculosis. To improve the physical chemical properties and drug-like parameters of this class of compounds, a medicinal chemistry effort was undertaken. By selecting the optimal substitution patterns for the phenyl rings at N1 and C5 and by replacing the thiomorpholine moiety with a morpholine one, a new series of compounds was produced. The replacement of the sulfur with oxygen gave compounds with lower lipophilicity and improved in vitro microsomal stability. Moreover, since the parent compound of this family has been shown to target MmpL3, mycobacterial mutants resistant to two compounds have been isolated and characterized by sequencing the mmpL3 gene; all the mutants showed point mutations in this gene. The best compound identified to date was progressed to dose-response studies in an acute murine TB infection model. The resulting ED(99) of 49 mg/Kg is within the range of commonly employed tuberculosis drugs, demonstrating the potential of this chemical series. The in vitro and in vivo target validation evidence presented here adds further weight to MmpL3 as a druggable target of interest for anti-tubercular drug discovery.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0056980PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578785PMC
August 2013

MmpL3 is the cellular target of the antitubercular pyrrole derivative BM212.

Antimicrob Agents Chemother 2012 Jan 24;56(1):324-31. Epub 2011 Oct 24.

Dipartimento di Genetica e Microbiologia, Universita degli Studi di Pavia, Pavia, Italy.

The 1,5-diarylpyrrole derivative BM212 was previously shown to be active against multidrug-resistant clinical isolates and Mycobacterium tuberculosis residing within macrophages as well as against Mycobacterium avium and other atypical mycobacteria. To determine its mechanism of action, we identified the cellular target. Spontaneous Mycobacterium smegmatis, Mycobacterium bovis BCG, and M. tuberculosis H37Rv mutants that were resistant to BM212 were isolated. By the screening of genomic libraries and by whole-genome sequencing, we found that all the characterized mutants showed mutations in the mmpL3 gene, allowing us to conclude that resistance to BM212 maps to the MmpL3 protein, a member of the MmpL (mycobacterial membrane protein, large) family. Susceptibility was unaffected by the efflux pump inhibitors reserpine, carbonylcyanide m-chlorophenylhydrazone, and verapamil. Uptake/efflux experiments with [(14)C]BM212 demonstrated that resistance is not driven by the efflux of BM212. Together, these data strongly suggest that the MmpL3 protein is the cellular target of BM212.
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http://dx.doi.org/10.1128/AAC.05270-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256021PMC
January 2012

Ungeremine effectively targets mammalian as well as bacterial type I and type II topoisomerases.

Bioorg Med Chem Lett 2011 Dec 1;21(23):7041-4. Epub 2011 Oct 1.

Dipartimento Farmaco Chimico Tecnologico, University of Cagliari, Cagliari, Italy.

From the methanol extract of the bulbs of Pancratium illyricum L., three phenanthridine type alkaloids, ungeremine (1), (-)-lycorine (2) and (+)-vittatine (3) were isolated. For the evaluation of their anticancer and antibacterial potential, compounds 1-3 were tested against human (I, IIα) and bacterial (IA, IV) topoisomerases. Our data demonstrated that ungeremine impairs the activity of both, human and bacterial topoisomerases. Remarkably, ungeremine was found to largely increments the DNA cleavage promoted by bacterial topoisomerase IA, a new target in antimicrobial chemotherapy.
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http://dx.doi.org/10.1016/j.bmcl.2011.09.097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551395PMC
December 2011

Developing pyrrole-derived antimycobacterial agents: a rational lead optimization approach.

ChemMedChem 2011 Apr 21;6(4):593-9. Epub 2011 Feb 21.

Dipartimento di Chimica e Tecnologia del Farmaco, Istituto Pasteur, Fondazione Cenci Bolognetti, Università degli Studi di Roma "La Sapienza", Piazzale A. Moro 5, 00185 Roma, Italy.

Tuberculosis (TB) represents a never-ending challenge toward which research efforts are needed. Drug resistance is the key problem that scientists in the field need to fight. The development of new drugs endowed with novel modes of action against different biological targets is of extreme importance; these new agents should also exhibit lower toxicity compared with the anti-TB drugs currently available. Furthermore, new drugs should be inexpensive since most of the TB-infected population lives in developing nations. In the last few years, numerous researchers have focused their attention on TB, leading to the discovery of some interesting compounds. Among these, the pyrrole-derived compounds we developed can be considered very promising antimycobacterial agents. Aided by molecular modeling studies, we synthesized numerous compounds characterized by the same 1,5-diarylpyrrole scaffold and elucidated very interesting antitubercular/antimycobacterial properties. Some compounds identified are extremely promising and represent a step towards the design of novel lead structures in the fight against TB. Our efforts to this end are reviewed here.
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http://dx.doi.org/10.1002/cmdc.201000526DOI Listing
April 2011

Identification of a novel pyrrole derivative endowed with antimycobacterial activity and protection index comparable to that of the current antitubercular drugs streptomycin and rifampin.

Bioorg Med Chem 2010 Nov 19;18(22):8076-84. Epub 2010 Sep 19.

Istituto Pasteur Fondazione Cenci-Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università La Sapienza, piazzale Aldo Moro 5, I-00185 Roma, Italy.

A hit optimization procedure based on isosteric and bioisosteric replacement of decorating groups at both the N1 and the C5 phenyl rings of 1,5-diarylpyrroles led to identification of 4-((1-(4-fluorophenyl)-2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-3-yl)methyl)thiomorpholine that is characterized by a very high activity toward both Mycobacterium tuberculosis 103471 and H37Rv strains (MIC values of 0.125μg/mL), and a safe profile in terms of cytotoxicity (CC(50) of >128μg/mL) and protection index (>1000). Antitubercular activity and protection index of the new compound are comparable to those found for the current antitubercular drugs streptomycin and rifampin.
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http://dx.doi.org/10.1016/j.bmc.2010.09.006DOI Listing
November 2010

1,5-Diaryl-2-ethyl pyrrole derivatives as antimycobacterial agents: design, synthesis, and microbiological evaluation.

Eur J Med Chem 2009 Nov 13;44(11):4734-8. Epub 2009 Jun 13.

Dipartimento di Chimica e Tecnologie del Farmaco, Università La Sapienza, I-00185 Roma, Italy.

During the search of novel antitubercular drugs related to BM 212, new diarylpyrroles were designed and synthesized on the basis of a structure-activity relationship analysis of many pyrroles previously described by us. Among them, 1-(4-fluorophenyl)-2-ethyl-3-(thiomorpholin-4-yl)methyl-5-(4-methylphenyl)-1H-pyrrole (2b) proved to be particularly active, with a minimum inhibitory concentration (MIC, expressed as microg/mL) and a protection index (PI) better than or comparable to those of reference compounds. Also the remaining compounds were very active, although their MIC and PI were in general lower than those of their parent 2-methyl analogues.
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http://dx.doi.org/10.1016/j.ejmech.2009.06.005DOI Listing
November 2009

Synthesis, biological evaluation, and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis: part 2. Synthesis of rigid pyrazolones.

Bioorg Med Chem 2009 Aug 29;17(15):5716-21. Epub 2009 May 29.

Università degli Studi di Siena, via A. De Gasperi 2, 53100 Siena, Italy.

Two series of novel rigid pyrazolone derivatives were synthesized and evaluated as inhibitors of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis. Two of these compounds showed a high activity against MTB (MIC=4 microg/mL). The newly synthesized pyrazolones were also computationally investigated to analyze if their properties fit the pharmacophoric model for antitubercular compounds previously built by us. The results are in agreement with those reported by us previously for a class of pyrazole analogues and confirm the fundamental role of the p-chlorophenyl moiety at C4 in the antimycobacterial activity.
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http://dx.doi.org/10.1016/j.bmc.2009.05.058DOI Listing
August 2009

Rifampicin-loaded liposomes for the passive targeting to alveolar macrophages: in vitro and in vivo evaluation.

J Liposome Res 2009 ;19(1):68-76

Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Cagliari, Cagliari, Italy.

Mycobacterium avium complex (MAC), the most frequent cause of opportunistic nontuberculous pulmonary infection, is made up of a group of intracellular pathogens that are able to survive and multiply inside lung alveolar macrophages. As nebulized liposomes are reported to be effective to target antibacterial agents to macrophages, in this work we have prepared and characterized re-dispersible freeze-dried rifampicin (RFP)-loaded vesicles by using soy lecithin (SL) and a commercial, enriched mixture of soy phosphatidylcholine (Phospholipon 90, P90) with or without cholesterol. The obtained results showed that RFP could be loaded stably in SL vesicles only when cholesterol was not present in the film preparation, whereas with P90 vesicles, the highest stability was obtained with formulations prepared with P90/cholesterol 7:1 or 4:1 molar ratios. RFP-liposome aerosols were generated using an efficient high-output continuous-flow nebulizer, driven by a compressor. After the experiments, nebulization efficiency (NE%) and nebulization efficiency of the encapsulated drug (NEED%) were evaluated. The results of our study indicated that nebulization properties and viscosity of formulations prepared with the low-transition-temperature phospholipids, SL and P90, are affected by vesicle composition. However, all formulations showed a good stability during nebulization and they were able to retain more than 65% of the incorporated drug. The effect of liposome encapsulation on lung levels of RFP following aerosol inhalation was determined in rats. The in vitro intracellular activity of RFP-loaded liposomes against MAC residing in macrophage-like J774 cells was also evaluated. Results indicated that liposomes are able to inhibit the growth of MAC in infected macrophages and to reach the lower airways in rats.
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http://dx.doi.org/10.1080/08982100802610835DOI Listing
October 2009

Synthesis and biological evaluation of new enantiomerically pure azole derivatives as inhibitors of Mycobacterium tuberculosis.

Bioorg Med Chem Lett 2009 Apr 28;19(8):2203-5. Epub 2009 Feb 28.

Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Siena, Italy.

A series of novel enantiomerically pure azole derivatives was synthesized. The new compounds, bearing both an imidazole as well as a triazole moiety, were evaluated as antimycobacterial agents. One of them proved to have activity against Mycobaterium tuberculosis comparable to those of the classical antibacterial/antifungal drugs Econazole and Clotrimazole.
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http://dx.doi.org/10.1016/j.bmcl.2009.02.101DOI Listing
April 2009

Novel N-aryl- and N-heteryl phenazine-1-carboxamides as potential agents for the treatment of infections sustained by drug-resistant and multidrug-resistant Mycobacterium tuberculosis.

Int J Antimicrob Agents 2009 Mar 13;33(3):223-9. Epub 2008 Dec 13.

Department of Sciences and Biomedical Technologies, Division of Medical Microbiology, University of Cagliari, Cagliari, Italy.

We investigated the in vitro activity of a new class of N-aryl and N-heteryl phenazine-1-carboxamide derivatives against Mycobacterium tuberculosis H37Rv and against drug-resistant ATCC M. tuberculosis strains. The activity against M. tuberculosis in J774 macrophage cells was also investigated. In most cases, minimum inhibitory concentrations (MICs) ranging between 0.19 mg/L and 0.79 mg/L were found, and comparable MIC values were obtained against 26 susceptible and 5 drug-resistant clinical isolates. Several derivatives were shown to be effective in inhibiting the growth both of susceptible and resistant strains at comparable concentrations. Results obtained indicate that these compounds could represent a promising class of agents useful for the treatment of M. tuberculosis infections caused by drug-resistant strains.
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http://dx.doi.org/10.1016/j.ijantimicag.2008.09.016DOI Listing
March 2009

2-Acylhydrazino-5-arylpyrrole derivatives: synthesis and antifungal activity evaluation.

Eur J Med Chem 2009 Mar 22;44(3):1288-95. Epub 2008 Aug 22.

Dipartimento di Tossicologia, Sezione di Chimica Farmaceutica, Università degli Studi di Cagliari, via Ospedale 72, Cagliari I-09124, Italy.

The synthesis and antifungal activity of 2-acylhydrazino-5-arylpyrroles 21-62 are described. Pyrrole derivatives 21-62 were evaluated for their antifungal activity towards Candida albicans ATCC 10231 and three Candida non-albicans isolated from clinical specimens. Most of them showed very good antifungal activities against Candidae, having MIC values in the 0.39-3.12 microg/mL range and enhanced inhibition potency as compared to that of fluconazole. In addition, some of the most active compounds were tested for cytotoxic activities against breast (MCF-7), lung (H-460), and central nervous system (SF-268) human cancer cell lines with the NCI anticancer drug screen. The activity of pyrroles described in this paper, along with the low toxicity, shows promise for the future development of non-toxic new antimycotic agents. The relationship between functional group variation and biological activity of the evaluated compounds is also discussed.
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http://dx.doi.org/10.1016/j.ejmech.2008.08.003DOI Listing
March 2009

Synthesis, biological evaluation and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis.

Bioorg Med Chem 2008 Sep 7;16(18):8587-91. Epub 2008 Aug 7.

Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy.

As a continuation of our previous work that turned toward the identification of antimycobacterial compounds with innovative structures, two series of pyrazole derivatives were synthesized by parallel solution-phase synthesis and were assayed as inhibitors of Mycobacterium tuberculosis (MTB), which is the causative agent of tuberculosis. One of these compounds showed high activity against MTB (MIC = 4 microg/mL). The newly synthesized pyrazoles were also computationally investigated to analyze their fit properties to the pharmacophoric model for antitubercular compounds previously built by us and to refine structure-activity relationship analysis.
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http://dx.doi.org/10.1016/j.bmc.2008.08.016DOI Listing
September 2008

1,5-Diphenylpyrrole derivatives as antimycobacterial agents. Probing the influence on antimycobacterial activity of lipophilic substituents at the phenyl rings.

J Med Chem 2008 Jun;51(12):3644-8

Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università La Sapienza, Piazzale A. Moro 5, I-00185 Rome, Italy.

Synthesis and biological evaluation of new derivatives of 1,5-bis(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM 212, 16) are reported. Variously substituted phenyl rings with different substitution pattern and lipophilicity were added to the pyrrole nucleus to evaluate their influence on the activity toward Mycobacterium tuberculosis (MTB) and atypical mycobacteria. The most active derivatives showed activity between 0.125-0.5 microg/mL (better than 16 and streptomycin) and protection index (64-256) higher than 16 (4) and similar to isoniazid and streptomycin (128).
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http://dx.doi.org/10.1021/jm701560pDOI Listing
June 2008

SLN as a topical delivery system for Artemisia arborescens essential oil: in vitro antiviral activity and skin permeation study.

Int J Nanomedicine 2007 ;2(3):419-25

Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Cagliari, Cagliari, Italy.

The effect of SLN incorporation on transdermal delivery and in vitro antiherpetic activity of Artemisia arborescens essential oil was investigated. Two different SLN formulations were prepared using the hot-pressure homogenization technique, Compritol 888 ATO as lipid, and Poloxamer 188 and Miranol Ultra C32 as surfactants. Formulations were examined for their stability for two years by monitoring average size distribution and zeta potential values. The antiviral activity of free and SLN incorporated essential oil was tested in vitro against Herpes Simplex Virus-1 (HSV-1) by a quantitative tetrazolium-based colorimetric method (MTT), while the effects of essential oil incorporation into SLN on both the permeation through and the accumulation into the skin strata was investigated by using in vitro diffusion experiments through newborn pig skin and an almond oil Artemisia essential oil solution as a control. Results showed that both SLN formulations were able to entrap the essential oil in high yields and that the mean particle size increased only slightly after two years of storage, indicating a high physical stability. In vitro antiviral assays showed that SLN incorporation did not affect the essential oil antiherpetic activity. The in vitro skin permeation experiments demonstrated the capability of SLN of greatly improving the oil accumulation into the skin, while oil permeation occurred only when the oil was delivered from the control solution.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676653PMC
December 2007

Antiherpevirus activity of Artemisia arborescens essential oil and inhibition of lateral diffusion in Vero cells.

Ann Clin Microbiol Antimicrob 2007 Sep 26;6:10. Epub 2007 Sep 26.

Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Microbiologia Medica, Viale Sant'Ignazio 38, 09123 Cagliari, Italy.

Background: New prophylactic and therapeutic tools are needed for the treatment of herpes simplex virus infections. Several essential oils have shown to possess antiviral activity in vitro against a wide spectrum of viruses.

Aim: The present study was assess to investigate the activities of the essential oil obtained from leaves of Artemisia arborescens against HSV-1 and HSV-2

Methods: The cytotoxicity in Vero cells was evaluated by the MTT reduction method. The IC50 values were determined by plaque reduction assay. In order to characterize the mechanism of action, yield reduction assay, inhibition of plaque development assay, attachment assay, penetration assay and post-attachment virus neutralization assay were also performed.

Results: The IC50 values, determined by plaque reduction assay, were 2.4 and 4.1 microg/ml for HSV-1 and HSV-2, respectively, while the cytotoxicity assay against Vero cells, as determined by the MTT reduction method, showed a CC50 value of 132 mug/ml, indicating a CC50/IC50 ratio of 55 for HSV-1 and 32.2 for HSV-2. The antiviral activity of A. arborescens essential oil is principally due to direct virucidal effects. A poor activity determined by yield reduction assay was observed against HSV-1 at higher concentrations when added to cultures of infected cells. No inhibition was observed by attachment assay, penetration assay and post-attachment virus neutralization assay. Furthermore, inhibition of plaque development assay showed that A. arborescens essential oil inhibits the lateral diffusion of both HSV-1 and HSV-2.

Conclusion: This study demonstrates the antiviral activity of the essential oil in toto obtained from A. arborescens against HSV-1 and HSV-2. The mode of action of the essential oil as antiherpesvirus agent seems to be particularly interesting in consideration of its ability to inactivate the virus and to inhibit the cell-to-cell virus diffusion.
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http://dx.doi.org/10.1186/1476-0711-6-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2099429PMC
September 2007

Ligand-based virtual screening, parallel solution-phase and microwave-assisted synthesis as tools to identify and synthesize new inhibitors of mycobacterium tuberculosis.

ChemMedChem 2006 Sep;1(9):973-89

Dipartimento Farmaco Chimico Tecnologico, Università Degli Studi di Siena, Via Alcide de Gasperi 2, 53100 Siena, Italy.

In an attempt to identify new inhibitors of the growth of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis, a procedure for the generation, design, and screening of a ligand-based virtual library was applied. This used both an in silico protocol centered on a recursive partitioning (RP) model described herein, and a pharmacophoric model for antitubercular agents previously generated by our research group. Two candidates emerged from databases of commercially available compounds, both characterized by a minimum inhibitory concentration (MIC) of 25 microg mL(-1). Based on these compounds, two series of derivatives were synthesized by both parallel solution-phase and microwave-assisted synthesis, leading to enhanced antimycobacterial activity. During both the design and synthesis, attention was focused on the efficient allocation of available resources with the aim of reducing the overall costs associated with calculation and synthesis.
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http://dx.doi.org/10.1002/cmdc.200600026DOI Listing
September 2006

In vitro antimycobacterial activity of newly synthesised S-alkylisothiosemicarbazone derivatives and synergistic interactions in combination with rifamycins against Mycobacterium avium.

Int J Antimicrob Agents 2005 Jul;26(1):28-32

Division of Medical Microbiology, Department of Biomedical Sciences and Technologies, University of Cagliari, Viale Sant'Ignazio 38, 09123 Cagliari, Italy.

The antimycobacterial activities of two new S-alkylisothiosemicarbazone derivatives (1i and 1f) against 32 Mycobacterium avium isolates were investigated. The minimum inhibitory concentrations (MICs) were significantly lower than those of rifampicin and other reference drugs. The two derivatives also showed excellent intracellular activity against M. avium residing in the macrophage-like J774 cells. Interestingly, the combination of subinhibitory concentrations of 1i and rifabutin or rifampicin induced a potent synergistic effect, as determined by the fractional inhibitory concentration indexes (FICIs) ranging between 0.103 and 0.412. Such synergistic effect resulted in a 81-fold and 139-fold reduction of the MICs of rifabutin and rifampicin, respectively. Enhancement of intracellular activity of rifabutin by the S-alkylisothiosemicarbazone derivative 1i was also observed. Results indicate that S-alkylisothiosemicarbazones can be useful in the therapy and prophylaxis of M. avium infections and can represent a template for the development of novel antimycobacterial drugs. Furthermore, as a consequence of their ability to enhance the activity of rifamycins, a reduction of drug interactions following the co-administration of protease inhibitors could be achieved by lower doses of rifampicin and rifabutin.
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http://dx.doi.org/10.1016/j.ijantimicag.2005.03.005DOI Listing
July 2005

In vitro activity of 2-cyclohexylidenhydrazo-4-phenyl-thiazole compared with those of amphotericin B and fluconazole against clinical isolates of Candida spp. and fluconazole-resistant Candida albicans.

J Antimicrob Chemother 2005 May 16;55(5):692-8. Epub 2005 Mar 16.

Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Microbiologia Medica, Università di Cagliari, Cagliari, Italy.

Objectives: The aim of this study was to investigate the in vitro antifungal activity of an isothiosemicarbazone cyclic analogue against isolates of Candida spp. including fluconazole-resistant Candida albicans.

Methods: We investigated the activity of 2-cyclohexylidenhydrazo-4-phenyl-thiazole (EM-01D2) against 114 clinical isolates of Candida spp., representing five different species, by microdilution, according to the NCCLS method 27-A. The activity against C. albicans biofilms was also investigated. Toxicity in vitro was evaluated by MTT reduction assay.

Results: EM-01D2 demonstrated low toxicity, broad spectrum, fungicidal activity and was active against C. albicans and Candida krusei at concentrations lower than those shown by amphotericin B and fluconazole (P < 0.05). It maintained potent in vitro activity against fluconazole-resistant C. albicans isolates. Fungicidal activity occurred at concentrations 1-2 doubling dilutions greater than the corresponding MICs, and time-kill analysis indicated that a 99.9% loss of C. albicans viability occurred after 6 h of incubation in the presence of EM-01D2 at concentrations equal to four times the MIC. EM-01D2 was also active in inhibiting the growth of C. albicans ATCC 10231 biofilms, even though such inhibition occurred at concentrations higher than the MICs determined under planktonic growth conditions. However, when C. albicans biofilms were pre-exposed to subinhibitory concentrations of EM-01D2, a reduction of MIC50 of amphotericin B was observed.

Conclusions: Based on these results, EM-01D2 could represent a template for the development of novel fungicidal agents.
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http://dx.doi.org/10.1093/jac/dki084DOI Listing
May 2005

Liposomal incorporation of Artemisia arborescens L. essential oil and in vitro antiviral activity.

Eur J Pharm Biopharm 2005 Jan;59(1):161-8

Dipartimento Farmaco Chimico Tecnologico, Università di Cagliari, Cagliari, Italy.

The effect of liposomal inclusion on the in vitro antiherpetic activity of Artemisia arborescens L. essential oil was investigated. In order to study the influence of vesicle structure and composition on the antiviral activity of the vesicle-incorporated oil, multilamellar (MLV) and unilamellar (SUV) positively charged liposomes were prepared by the film method and sonication. Liposomes were obtained from hydrogenated (P90H) and non-hydrogenated (P90) soy phosphatidylcholine. Formulations were examined for their stability for over one year, monitoring the oil leakage from vesicles and the average size distribution. The antiviral activity was studied against Herpes simplex virus type 1 (HSV-1) by a quantitative tetrazolium-based colorimetric method. Results showed that Artemisia essential oil can be incorporated in good amounts in the prepared vesicular dispersions. Stability studies pointed out that vesicle dispersions were very stable for at least six months and neither oil leakage nor vesicle size alteration occurred during this period. After one year of storage oil retention was still good, but vesicle fusion was present. Antiviral assays demonstrated that the liposomal incorporation of A. arborescens essential oil enhanced its in vitro antiherpetic activity especially when vesicles were made with P90H. On the contrary, no significant difference in antiviral activity was observed between the free and SUV-incorporated oil.
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http://dx.doi.org/10.1016/j.ejpb.2004.06.005DOI Listing
January 2005
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