Publications by authors named "Chiara Borsari"

27 Publications

  • Page 1 of 1

Chemical and Structural Strategies to Selectively Target mTOR Kinase.

ChemMedChem 2021 Jun 11. Epub 2021 Jun 11.

University of Basel: Universitat Basel, Department of Biomedicine, Mattenstrasse 28, 4058, Basel, SWITZERLAND.

Dysregulation of the mechanistic target of rapamycin (mTOR) pathway is implicated in cancer and neurological disorder, which identifies mTOR inhibition as promising strategy for the treatment of a variety of human disorders. First-generation mTOR inhibitors include rapamycin and its analogues (rapalogs) which act as allosteric inhibitors of TORC1. Structurally unrelated, ATP-competitive inhibitors that directly target the mTOR catalytic site inhibit both TORC1 and TORC2. Here, we review investigations of chemical scaffolds explored for the development of highly selective ATP-competitive mTOR kinase inhibitors (TORKi). Extensive medicinal chemistry campaigns allowed to overcome challenges related to structural similarity between mTOR and the phosphoinositide 3-kinase (PI3K) family. A broad region of chemical space is covered by TORKi. Here, the investigation of chemical substitutions and physicochemical properties has shed light on the compounds' ability to cross the blood brain barrier (BBB). This work provides insights supporting the optimization of TORKi for the treatment of cancer and central nervous system disorders.
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http://dx.doi.org/10.1002/cmdc.202100332DOI Listing
June 2021

Second-generation tricyclic pyrimido-pyrrolo-oxazine mTOR inhibitor with predicted blood-brain barrier permeability.

RSC Med Chem 2021 Jan 12;12(4):579-583. Epub 2021 Jan 12.

Department of Biomedicine, University of Basel Mattenstrasse 28 4058 Basel Switzerland

Highly selective mTOR inhibitors have been discovered through the exploration of the heteroaromatic ring engaging the binding affinity region in mTOR kinase. Compound showed predicted BBB permeability in a MDCK-MDR1 permeability assay, being the first pyrimido-pyrrolo-oxazine with potential application in the treatment of neurological disorders.
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http://dx.doi.org/10.1039/d0md00408aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128076PMC
January 2021

Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors.

Elife 2021 Mar 4;10. Epub 2021 Mar 4.

Department of Biochemistry and Microbiology, University of Victoria, Victoria, Canada.

Class I Phosphoinositide 3-kinases (PI3Ks) are master regulators of cellular functions, with the class IB PI3K catalytic subunit (p110γ) playing key roles in immune signalling. p110γ is a key factor in inflammatory diseases and has been identified as a therapeutic target for cancers due to its immunomodulatory role. Using a combined biochemical/biophysical approach, we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of R1021 in the C-terminus can inactivate or activate enzyme activity. Screening of inhibitors using HDX-MS revealed that activation loop-binding inhibitors induce allosteric conformational changes that mimic those in the R1021C mutant. Structural analysis of advanced PI3K inhibitors in clinical development revealed novel binding pockets that can be exploited for further therapeutic development. Overall, this work provides unique insights into regulatory mechanisms that control PI3Kγ kinase activity and shows a framework for the design of PI3K isoform and mutant selective inhibitors.
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http://dx.doi.org/10.7554/eLife.64691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955810PMC
March 2021

4-(Difluoromethyl)-5-(4-((3,5)-3,5-dimethylmorpholino)-6-(()-3-methylmorpholino)-1,3,5-triazin-2-yl)pyridin-2-amine (PQR626), a Potent, Orally Available, and Brain-Penetrant mTOR Inhibitor for the Treatment of Neurological Disorders.

J Med Chem 2020 11 9;63(22):13595-13617. Epub 2020 Nov 9.

Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.

The mechanistic target of rapamycin (mTOR) pathway is hyperactivated in cancer and neurological disorders. Rapalogs and mTOR kinase inhibitors (TORKi) have recently been applied to alleviate epileptic seizures in tuberous sclerosis complex (TSC). Herein, we describe a pharmacophore exploration to identify a highly potent, selective, brain penetrant TORKi. An extensive investigation of the morpholine ring engaging the mTOR solvent exposed region led to the discovery of PQR626 (). displayed excellent brain penetration and was well-tolerated in mice. In mice with a conditionally inactivated gene in glia, significantly reduced the loss of -induced mortality at 50 mg/kg p.o. twice a day. overcomes the metabolic liabilities of PQR620 (), the first-in-class brain penetrant TORKi showing efficacy in a TSC mouse model. The improved stability in human hepatocytes, excellent brain penetration, and efficacy in CKO mice qualify as a potential therapeutic candidate for the treatment of neurological disorders.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00620DOI Listing
November 2020

Novel Dithiolane-Based Ligands Combining Sigma and NMDA Receptor Interactions as Potential Neuroprotective Agents.

ACS Med Chem Lett 2020 May 3;11(5):1028-1034. Epub 2020 Apr 3.

Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy.

Sigma receptors (SRs) are recognized as valuable targets for the treatment of neurodegenerative disorders. A series of novel SRs ligands were designed by combining key pharmacophoric amines (i.e., benzylpiperidine or benzylpiperazine) with new 1,3-dithiolane-based heterocycles and their bioisosters. The new compounds exhibited a low nanomolar affinity for sigma-1 and sigma-2 receptors. Five selected compounds were evaluated for their neuroprotective capacity on SH-SY5Y neuroblastoma cell line. They were able to counteract the neurotoxicity induced by rotenone, oligomycin and NMDA. Competition studies with PB212, a S1R antagonist, confirmed the involvement of S1R in neuroprotection from the oxidative stress induced by rotenone. Electrophysiological experiments performed on cortical neurons in culture highlighted the compounds ability to reduce NMDA-evoked currents, suggesting a negative allosteric modulator activity toward the NMDA receptor. Altogether these results qualify our novel dithiolane derivatives as potential agents for fighting neurodegeneration.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236556PMC
May 2020

Designing Chimeric Molecules for Drug Discovery by Leveraging Chemical Biology.

J Med Chem 2020 03 19;63(5):1908-1928. Epub 2020 Feb 19.

Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy.

After the first seed concept introduced in the 18th century, different disciplines have attributed different names to dual-functional molecules depending on their application, including bioconjugates, bifunctional compounds, multitargeting molecules, chimeras, hybrids, engineered compounds. However, these engineered constructs share a general structure: a first component that targets a specific cell and a second component that exerts the pharmacological activity. A stable or cleavable linker connects the two modules of a chimera. Herein, we discuss the recent advances in the rapidly expanding field of chimeric molecules leveraging chemical biology concepts. This Perspective is focused on bifunctional compounds in which one component is a lead compound or a drug. In detail, we discuss chemical features of chimeric molecules and their use for targeted delivery and for target engagement studies.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997565PMC
March 2020

Identification of a 2,4-diaminopyrimidine scaffold targeting Trypanosoma brucei pteridine reductase 1 from the LIBRA compound library screening campaign.

Eur J Med Chem 2020 Mar 10;189:112047. Epub 2020 Jan 10.

Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125, Modena, Italy. Electronic address:

The LIBRA compound library is a collection of 522 non-commercial molecules contributed by various Italian academic laboratories. These compounds have been designed and synthesized during different medicinal chemistry programs and are hosted by the Italian Institute of Technology. We report the screening of the LIBRA compound library against Trypanosoma brucei and Leishmania major pteridine reductase 1, TbPTR1 and LmPTR1. Nine compounds were active against parasitic PTR1 and were selected for cell-based parasite screening, as single agents and in combination with methotrexate (MTX). The most interesting TbPTR1 inhibitor identified was 4-(benzyloxy)pyrimidine-2,6-diamine (LIB_66). Subsequently, six new LIB_66 derivatives were synthesized to explore its Structure-Activity-Relationship (SAR) and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. The results indicate that PTR1 has a preference to bind inhibitors, which resemble its biopterin/folic acid substrates, such as the 2,4-diaminopyrimidine derivatives.
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http://dx.doi.org/10.1016/j.ejmech.2020.112047DOI Listing
March 2020

Preclinical Development of PQR514, a Highly Potent PI3K Inhibitor Bearing a Difluoromethyl-Pyrimidine Moiety.

ACS Med Chem Lett 2019 Oct 3;10(10):1473-1479. Epub 2019 Sep 3.

Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.

The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway is a critical regulator of cell growth and is frequently hyperactivated in cancer. Therefore, PI3K inhibitors represent a valuable asset in cancer therapy. Herein we have developed a novel anticancer agent, the potent pan-PI3K inhibitor PQR514 (), which is a follow-up compound for the phase-II clinical compound PQR309 (). Compound has an improved potency both in vitro and in cellular assays with respect to its predecessor compounds. It shows superiority in the suppression of cancer cell proliferation and demonstrates significant antitumor activity in an OVCAR-3 xenograft model at concentrations approximately eight times lower than PQR309 (). The favorable pharmacokinetic profile and a minimal brain penetration promote PQR514 () as an optimized candidate for the treatment of systemic tumors.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792169PMC
October 2019

Discovery of a benzothiophene-flavonol halting miltefosine and antimonial drug resistance in Leishmania parasites through the application of medicinal chemistry, screening and genomics.

Eur J Med Chem 2019 Dec 5;183:111676. Epub 2019 Sep 5.

University of Modena and Reggio Emilia, Via Campi 103, 41125, Modena, Italy. Electronic address:

Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC 1.9 μM for Leishmania infantum, 3.4 μM for L. donovani, 6.7 μM for L. major), Trypanosoma cruzi (EC 7.5 μM) and T. brucei (EC 0.8 μM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.
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http://dx.doi.org/10.1016/j.ejmech.2019.111676DOI Listing
December 2019

A Conformational Restriction Strategy for the Identification of a Highly Selective Pyrimido-pyrrolo-oxazine mTOR Inhibitor.

J Med Chem 2019 09 11;62(18):8609-8630. Epub 2019 Sep 11.

Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.

The mechanistic target of rapamycin (mTOR) plays a pivotal role in growth and tumor progression and is an attractive target for cancer treatment. ATP-competitive mTOR kinase inhibitors (TORKi) have the potential to overcome limitations of rapamycin derivatives in a wide range of malignancies. Herein, we exploit a conformational restriction approach to explore a novel chemical space for the generation of TORKi. Structure-activity relationship (SAR) studies led to the identification of compound with a ∼450-fold selectivity for mTOR over class I PI3K isoforms. Pharmacokinetic studies in male Sprague Dawley rats highlighted a good exposure after oral dosing and a minimum brain penetration. CYP450 reactive phenotyping pointed out the high metabolic stability of . These results identify the tricyclic pyrimido-pyrrolo-oxazine moiety as a novel scaffold for the development of highly selective mTOR inhibitors for cancer treatment.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00972DOI Listing
September 2019

()-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase.

J Med Chem 2019 07 20;62(13):6241-6261. Epub 2019 Jun 20.

Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.

The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway is frequently overactivated in cancer, and drives cell growth, proliferation, survival, and metastasis. Here, we report a structure-activity relationship study, which led to the discovery of a drug-like adenosine 5'-triphosphate-site PI3K/mTOR kinase inhibitor: ()-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530, compound ), which qualifies as a clinical candidate due to its potency and specificity for PI3K and mTOR kinases, and its pharmacokinetic properties, including brain penetration. Compound showed excellent selectivity over a wide panel of kinases and an excellent selectivity against unrelated receptor enzymes and ion channels. Moreover, compound prevented cell growth in a cancer cell line panel. The preclinical in vivo characterization of compound in an OVCAR-3 xenograft model demonstrated good oral bioavailability, excellent brain penetration, and efficacy. Initial toxicity studies in rats and dogs qualify for further development as a therapeutic agent in oncology.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00525DOI Listing
July 2019

Structural Insights into the Development of Cycloguanil Derivatives as Pteridine-Reductase-1 Inhibitors.

ACS Infect Dis 2019 07 1;5(7):1105-1114. Epub 2019 May 1.

Department of Biotechnology, Chemistry and Pharmacy-Department of Excellence 2018-2020 , University of Siena , via Aldo Moro 2 , 53100 Siena , Italy.

Cycloguanil is a known dihydrofolate-reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of PTR1 (PTR1). A small library of cycloguanil derivatives was developed, resulting in and having IC values of 692 and 186 nM, respectively, toward PTR1. Structural analysis revealed that the increased potency of and is due to the combined contributions of hydrophobic interactions, H-bonds, and halogen bonds. Moreover, cell-growth-inhibition tests indicated that is also effective on . The simultaneous inhibition of DHFR and PTR1 activity in is a promising new strategy for the treatment of human African trypanosomiasis. For this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.
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http://dx.doi.org/10.1021/acsinfecdis.8b00358DOI Listing
July 2019

SAR Studies and Biological Characterization of a Chromen-4-one Derivative as an Anti- Agent.

ACS Med Chem Lett 2019 Apr 29;10(4):528-533. Epub 2019 Jan 29.

University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy.

Chemical modulation of the flavonol 2-(benzo[d][1,3]dioxol-5-yl)-chromen-4-one (), a promising anti-Trypanosomatid agent previously identified, was evaluated through a phenotypic screening approach. Herein, we have performed structure-activity relationship studies around hit compound . The pivaloyl derivative () showed significant anti- activity (EC = 1.1 μM) together with a selectivity index higher than 92. The early ADME-tox properties (cytotoxicity, mitochondrial toxicity, cytochrome P450 and ERG inhibition) were determined for compound and its derivatives, and these led to the identification of some liabilities. The 1,3-benzodioxole moiety in the presented compounds confers better in vivo pharmacokinetic properties than those of classical flavonols. Further studies using different delivery systems could lead to an increase of compound blood levels.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466517PMC
April 2019

Excited-state intramolecular proton transfer in a bioactive flavonoid provides fluorescence observables for recognizing its engagement with target proteins.

Photochem Photobiol Sci 2019 Sep 22;18(9):2270-2280. Epub 2019 Mar 22.

Department of Life Sciences, University of Modena and Reggio Emilia (UNIMORE), Via Campi 103, 41125 Modena, Italy.

A benzothiophene-substituted chromenone with promising activity against Leishmania and Trypanosoma species exhibits peculiar fluorescence properties useful for identifying its complexes with target proteins in the microorganism proteomes. The emission spectra, anisotropy and time profiles of this flavonoid strongly change when moving from the free to the protein-bound forms. The same two types of emission are observed in organic solvents and their mixtures with water, with the relative band intensities depending on the solvent ability to establish hydrogen bonds with the solute. The regular emission prevails in protic solvents, while in aprotic solvents the anomalously red-shifted emission occurs from a zwitterionic tautomeric form, produced in the excited state by proton transfer within the intramolecularly H-bonded form. This interpretation finds support from an experimental and theoretical investigation of the conformational preferences of this compound in the ground and lowest excited state, with a focus on the relative twisting about the chromenone-benzothiophene interconnecting bond. An analysis of the absorption and emission spectra and of the photophysical properties of the two emitting tautomers highlights the relevance of the local microenvironment, particularly of the intra- and intermolecular hydrogen bonds in which this bioactive compound is involved, in determining both its steady-state and time-resolved fluorescence behaviour.
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http://dx.doi.org/10.1039/c9pp00026gDOI Listing
September 2019

Accelerating Drug Discovery Efforts for Trypanosomatidic Infections Using an Integrated Transnational Academic Drug Discovery Platform.

SLAS Discov 2019 03;24(3):346-361

14 Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany.

According to the World Health Organization, more than 1 billion people are at risk of or are affected by neglected tropical diseases. Examples of such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all of which are prevalent in Africa, South America, and India. Our aim within the New Medicines for Trypanosomatidic Infections project was to use (1) synthetic and natural product libraries, (2) screening, and (3) a preclinical absorption, distribution, metabolism, and excretion-toxicity (ADME-Tox) profiling platform to identify compounds that can enter the trypanosomatidic drug discovery value chain. The synthetic compound libraries originated from multiple scaffolds with known antiparasitic activity and natural products from the Hypha Discovery MycoDiverse natural products library. Our focus was first to employ target-based screening to identify inhibitors of the protozoan Trypanosoma brucei pteridine reductase 1 ( TbPTR1) and second to use a Trypanosoma brucei phenotypic assay that made use of the T. brucei brucei parasite to identify compounds that inhibited cell growth and caused death. Some of the compounds underwent structure-activity relationship expansion and, when appropriate, were evaluated in a preclinical ADME-Tox assay panel. This preclinical platform has led to the identification of lead-like compounds as well as validated hits in the trypanosomatidic drug discovery value chain.
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http://dx.doi.org/10.1177/2472555218823171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484532PMC
March 2019

Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders.

J Med Chem 2018 11 14;61(22):10084-10105. Epub 2018 Nov 14.

Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.

Mechanistic target of rapamycin (mTOR) promotes cell proliferation, growth, and survival and is overactivated in many tumors and central nervous system disorders. PQR620 (3) is a novel, potent, selective, and brain penetrable inhibitor of mTORC1/2 kinase. PQR620 (3) showed excellent selectivity for mTOR over PI3K and protein kinases and efficiently prevented cancer cell growth in a 66 cancer cell line panel. In C57BL/6J and Sprague-Dawley mice, maximum concentration ( C) in plasma and brain was reached after 30 min, with a half-life ( t) > 5 h. In an ovarian carcinoma mouse xenograft model (OVCAR-3), daily dosing of PQR620 (3) inhibited tumor growth significantly. Moreover, PQR620 (3) attenuated epileptic seizures in a tuberous sclerosis complex (TSC) mouse model. In conclusion, PQR620 (3) inhibits mTOR kinase potently and selectively, shows antitumor effects in vitro and in vivo, and promises advantages in CNS indications due to its brain/plasma distribution ratio.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01262DOI Listing
November 2018

Development of a Focused Library of Triazole-Linked Privileged-Structure-Based Conjugates Leading to the Discovery of Novel Phenotypic Hits against Protozoan Parasitic Infections.

ChemMedChem 2018 04 16;13(7):678-683. Epub 2018 Feb 16.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.

Protozoan infections caused by Plasmodium, Leishmania, and Trypanosoma spp. contribute significantly to the burden of infectious diseases worldwide, causing severe morbidity and mortality. The inadequacy of available treatments calls for cost- and time-effective drug discovery endeavors. To this end, we envisaged the triazole linkage of privileged structures as an effective drug design strategy to generate a focused library of high-quality compounds. The versatility of this approach was combined with the feasibility of a phenotypic assay, integrated with early ADME-tox profiling. Thus, an 18-membered library was efficiently assembled via Huisgen cycloaddition of phenothiazine, biphenyl, and phenylpiperazine scaffolds. The resulting 18 compounds were then tested against seven parasite strains, and counter-screened for selectivity against two mammalian cell lines. In parallel, hERG and cytochrome P450 (CYP) inhibition, and mitochondrial toxicity were assessed. Remarkably, 10-((1-(3-([1,1'-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-5-yl)methyl)-10H-phenothiazine (7) and 10-(3-(1-(3-([1,1'-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-4-yl)propyl)-10H-phenothiazine (12) showed respective IC values of 1.8 and 1.9 μg mL against T. cruzi, together with optimal selectivity. In particular, compound 7 showed a promising ADME-tox profile. Thus, hit 7 might be progressed as an antichagasic lead.
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http://dx.doi.org/10.1002/cmdc.201700786DOI Listing
April 2018

Crassiflorone derivatives that inhibit Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR) and display trypanocidal activity.

Eur J Med Chem 2017 Dec 3;141:138-148. Epub 2017 Oct 3.

Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6 and Via Irnerio 48, 40126 Bologna, Italy. Electronic address:

Crassiflorone is a natural product with anti-mycobacterial and anti-gonorrhoeal properties, isolated from the stem bark of the African ebony tree Diospyros crassiflora. We noticed that its pentacyclic core possesses structural resemblance to the quinone-coumarin hybrid 3, which we reported to exhibit a dual-targeted inhibitory profile towards Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR). Following this basic idea, we synthesized a small library of crassiflorone derivatives 15-23 and investigated their potential as anti-trypanosomatid agents. 19 is the only compound of the series showing a balanced dual profile at 10 μM (% inhibition = 64% and % inhibition = 65%). In phenotypic assay, the most active compounds were 18 and 21, which at 5 μM inhibited Tb bloodstream-form growth by 29% and 38%, respectively. Notably, all the newly synthesized compounds at 10 μM did not affect viability and the status of mitochondria in human A549 and 786-O cell lines, respectively. However, further optimization that addresses metabolic liabilities including solubility, as well as cytochromes P450 (CYP1A2, CYP2C9, CYP2C19, and CYP2D6) inhibition, is required before this class of natural product-derived compounds can be further progressed.
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http://dx.doi.org/10.1016/j.ejmech.2017.10.005DOI Listing
December 2017

5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.

J Med Chem 2017 09 1;60(17):7524-7538. Epub 2017 Sep 1.

Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland.

Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656176PMC
September 2017

Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity.

Molecules 2017 Mar 8;22(3). Epub 2017 Mar 8.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy.

Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (-) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes ( PTR1-PTR1 and PTR1) and parasites ( and ). A crystal structure of PTR1 in complex with compound and the first crystal structures of PTR1-flavanone complexes (compounds and ) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants.
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http://dx.doi.org/10.3390/molecules22030426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155272PMC
March 2017

Methoxylated 2'-hydroxychalcones as antiparasitic hit compounds.

Eur J Med Chem 2017 Jan 9;126:1129-1135. Epub 2016 Dec 9.

University of Modena and Reggio Emilia, Via Campi 103, 41125, Modena, Italy. Electronic address:

Chalcones display a broad spectrum of pharmacological activities. Herein, a series of 2'-hydroxy methoxylated chalcones was synthesized and evaluated towards Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum. Among the synthesized library, compounds 1, 3, 4, 7 and 8 were the most potent and selective anti-T. brucei compounds (EC = 1.3-4.2 μM, selectivity index >10-fold). Compound 4 showed the best early-tox and antiparasitic profile. The pharmacokinetic studies of compound 4 in BALB/c mice using hydroxypropil-β-cyclodextrins formulation showed a 7.5 times increase in oral bioavailability.
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http://dx.doi.org/10.1016/j.ejmech.2016.12.017DOI Listing
January 2017

Target-based approaches for the discovery of new antimycobacterial drugs.

Drug Discov Today 2017 03 23;22(3):576-584. Epub 2016 Nov 23.

Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125 Modena, Italy; Tydock Pharma srl, Strada Gherbella 294/B, Modena 41126, Italy. Electronic address:

Tuberculosis (TB) is a major global health problem and control of the disease is hampered by the increasing emergence of multidrug resistance (MDR) strains. Novel drugs are urgently needed to overcome drug resistance. Among the most relevant targets of the past 3 years, herein we consider nine enzymes that have been studied in a target-based approach. These targets are involved mainly in the biosynthesis of the cell wall, α-glucan, coenzyme A and acyl carrier protein precursor, and in energy production, DNA metabolism, and pyrimidine synthesis. Some leads and many hits have been discovered using a target-based approach and can be further developed in a drug discovery process.
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http://dx.doi.org/10.1016/j.drudis.2016.11.014DOI Listing
March 2017

Virtual Screening and X-ray Crystallography Identify Non-Substrate Analog Inhibitors of Flavin-Dependent Thymidylate Synthase.

J Med Chem 2016 10 29;59(19):9269-9275. Epub 2016 Sep 29.

Department of Life Sciences, University of Modena and Reggio Emilia , Via Campi, 103, 41125 Modena, Italy.

Thymidylate synthase X (ThyX) represents an attractive target for tuberculosis drug discovery. Herein, we selected 16 compounds through a virtual screening approach. We solved the first X-ray crystal structure of Thermatoga maritima (Tm) ThyX in complex with a nonsubstrate analog inhibitor. Given the active site similarities between Mycobacterium tuberculosis ThyX (Mtb-ThyX) and Tm-ThyX, our crystal structure paves the way for a structure-based design of novel antimycobacterial compounds. The 1H-imidazo[4,5-d]pyridazine was identified as scaffold for the development of Mtb-ThyX inhibitors.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00977DOI Listing
October 2016

X-ray crystal structures of Enterococcus faecalis thymidylate synthase with folate binding site inhibitors.

Eur J Med Chem 2016 Nov 29;123:649-664. Epub 2016 Jul 29.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy. Electronic address:

Infections caused by Enterococcus faecalis (Ef) represent nowadays a relevant health problem. We selected Thymidylate synthase (TS) from this organism as a potential specific target for antibacterial therapy. We have previously demonstrated that species-specific inhibition of the protein can be achieved despite the relatively high structural similarity among bacterial TSs and human TS. We had previously obtained the EfTS crystal structure of the protein in complex with the metabolite 5-formyl-tetrahydrofolate (5-FTHF) suggesting the protein role as metabolite reservoir; however, protein-inhibitors complexes were still missing. In the present work we identified some inhibitors bearing the phthalimidic core from our in-house library and we performed crystallographic screening towards EfTS. We obtained two X-ray crystallographic structures: the first with a weak phthalimidic inhibitor bound in one subunit and 5-hydroxymethylene-6-hydrofolic acid (5-HMHF) in the other subunit; a second X-ray structure complex with methotrexate. The structural information achieved confirm the role of EfTS as an enzyme involved in the folate pool system and provide a structural basis for structure-based drug design.
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http://dx.doi.org/10.1016/j.ejmech.2016.07.066DOI Listing
November 2016

Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs.

J Med Chem 2016 08 5;59(16):7598-616. Epub 2016 Aug 5.

Complutense University of Madrid , 28040 Madrid, Spain.

Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 μM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 μM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00698DOI Listing
August 2016

Comparing Drug Images and Repurposing Drugs with BioGPS and FLAPdock: The Thymidylate Synthase Case.

ChemMedChem 2016 08 12;11(15):1653-66. Epub 2016 Jul 12.

Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125, Modena, Italy.

Repurposing and repositioning drugs has become a frequently pursued and successful strategy in the current era, as new chemical entities are increasingly difficult to find and get approved. Herein we report an integrated BioGPS/FLAPdock pipeline for rapid and effective off-target identification and drug repurposing. Our method is based on the structural and chemical properties of protein binding sites, that is, the ligand image, encoded in the GRID molecular interaction fields (MIFs). Protein similarity is disclosed through the BioGPS algorithm by measuring the pockets' overlap according to which pockets are clustered. Co-crystallized and known ligands can be cross-docked among similar targets, selected for subsequent in vitro binding experiments, and possibly improved for inhibitory potency. We used human thymidylate synthase (TS) as a test case and searched the entire RCSB Protein Data Bank (PDB) for similar target pockets. We chose casein kinase IIα as a control and tested a series of its inhibitors against the TS template. Ellagic acid and apigenin were identified as TS inhibitors, and various flavonoids were selected and synthesized in a second-round selection. The compounds were demonstrated to be active in the low-micromolar range.
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http://dx.doi.org/10.1002/cmdc.201600121DOI Listing
August 2016

Scouting new sigma receptor ligands: Synthesis, pharmacological evaluation and molecular modeling of 1,3-dioxolane-based structures and derivatives.

Eur J Med Chem 2016 Apr 1;112:1-19. Epub 2016 Feb 1.

Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy. Electronic address:

Herein we report the synthesis and biological activity of new sigma receptor (σR) ligands obtained by combining different substituted five-membered heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified 25b (1-(1,4-dioxaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperazine) as the most interesting compound of the series, displaying high affinity and selectivity for σ1R (pKiσ1 = 9.13; σ1/σ2 = 47). The ability of 25b to modulate the analgesic effect of the κ agonist (-)-U-50,488H and μ agonist morphine was evaluated in vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on both κ and μ receptor-mediated analgesia, suggesting an agonistic behavior at σ1R. Docking studies were performed on the theoretical σ1R homology model. The present work represents a new starting point for the design of more potent and selective σ1R ligands.
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http://dx.doi.org/10.1016/j.ejmech.2016.01.059DOI Listing
April 2016