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

Borsari, Chiara; Jiménez-Antón, María Dolores; Eick, Julia; Bifeld, Eugenia; Torrado, Juan J.; Olías-Molero, Ana Isabel; Corral, María Jesús; Baptista, Catarina; Severi, Leda; Gul, Sheraz; Wolf, Markus; Kuzikov, Maria; Ellinger, Bernhard; Reinshagen, Jeanette; Witt, Gesa; Linciano, Pasquale; Tait, Annalisa; Costantino, Luca; Luciani, Rosaria; Nevado, Paloma Tejera; Zander-Dinse, Dorothea; Franco, Caio Haddad; Ferrari, Stefania; Moraes, Carolina Borsoi; Cordeiro-da-Silva, Anabela; Ponterini, Glauco; Clos, Joachim; Alunda, José María; Costi, Maria Paola

doi:10.1016/j.ejmech.2019.111676

Cited by 20 publications

(16 citation statements)

References 44 publications

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“…In a water-mediated phosphorylative cyclodehydrogenation, flavones and flavanones can be synthesized in the same condition with the product type controlled by dosage of reagent [173]. As the oxidative state of flavones, flavonols can be produced from flavones by the oxidation with 3,3-dimethyldioxirane (DMDO) [174] or Algar-Flynn-Oyamada reaction in the presence of base and hydrogen peroxide [175,176], which may generate by-product of aurone due to the different attacking position of epoxide [177]. Selective synthesis of Scheme 17 Total-synthetic strategies of flavonoids by cyclization of 2'-hydroxychalcones aurone could be achieved through oxidative cyclization of 2'-hydroxychalcones mediated by Hg(OAc) 2 in a good yield [178,179].…”

Section: Total-synthesis Strategies Of Flavonoid Derivativesmentioning

confidence: 99%

Structural derivatization strategies of natural phenols by semi-synthesis and total-synthesis

Ding

Jiang

Zhang

et al. 2022

Nat. Prod. Bioprospect.

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Structural derivatization of natural products has been a continuing and irreplaceable source of novel drug leads. Natural phenols are a broad category of natural products with wide pharmacological activity and have offered plenty of clinical drugs. However, the structural complexity and wide variety of natural phenols leads to the difficulty of structural derivatization. Skeleton analysis indicated most types of natural phenols can be structured by the combination and extension of three common fragments containing phenol, phenylpropanoid and benzoyl. Based on these fragments, the derivatization strategies of natural phenols were unified and comprehensively analyzed in this review. In addition to classical methods, advanced strategies with high selectivity, efficiency and practicality were emphasized. Total synthesis strategies of typical fragments such as stilbenes, chalcones and flavonoids were also covered and analyzed as the supplementary for supporting the diversity-oriented derivatization of natural phenols.

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Section: Total-synthesis Strategies Of Flavonoid Derivativesmentioning

confidence: 99%

Structural derivatization strategies of natural phenols by semi-synthesis and total-synthesis

Ding

Jiang

Zhang

et al. 2022

Nat. Prod. Bioprospect.

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“…The TbPTR1 and LmPTR1 proteins were purified as reported previously [23]. The in-vitro coupled enzyme assays for each enzyme have also been reported in the literature and have independently been shown to be suitable for screening purposes [25,27,36,57,[64][65][66][67]. For each compound IC 50 , pIC 50 values and Hill Slope were determined using a 4-parameter logistic fit in the XE module of ActivityBase (IDBS).…”

Section: Molecular Modellingmentioning

confidence: 99%

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

Linciano

Cullia

Borsari

et al. 2020

European Journal of Medicinal Chemistry

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The LIBRA compound library is a collection of 522 noncommercial 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-2,6diamine (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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“…Amphotericin B is recommended to treat CL caused by L. tropica , L. braziliensis , L. major and L. aethiopica but not for L. infantum [ 12 – 16 ]. Further, as there are co-infections with different Leishmania species, it will lead to different pathogenicity and drug sensitivity which make the treatment more complicated [ 17 , 18 ]. Thus, Leishmania species identification is important in treatment and patient management, including pharmaceutical selection, appropriate treatment determination (intralesional, intramuscular, oral systemic, or parenteral) and monitoring potential infection sequelae [ 19 – 22 ].…”

Section: Introductionmentioning

confidence: 99%

Establish an allele-specific real-time PCR for Leishmania species identification

Jiang

et al. 2022

Infect Dis Poverty

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Background Leishmaniasis is a serious neglected tropical disease that may lead to life-threatening outcome, which species are closely related to clinical diagnosis and patient management. The current Leishmania species determination method is not appropriate for clinical application. New Leishmania species identification tool is needed using clinical samples directly without isolation and cultivation of parasites. Methods A probe-based allele-specific real-time PCR assay was established for Leishmania species identification between Leishmania donovani and L. infantum for visceral leishmaniasis (VL) and among L. major, L. tropica and L. donovani/L. infantum for cutaneous leishmaniasis (CL), targeting hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and spermidine synthase (SPDSYN) gene with their species-specific single nucleotide polymorphisms (SNPs). The limit of detection of this assay was evaluated based on 8 repeated tests with intra-assay standard deviation < 0.5 and inter-assay coefficients of variability < 5%. The specificity of this assay was tested with DNA samples obtained from Plasmodium falciparum, Toxoplasma gondii, Brucella melitensis and Orientia tsutsugamushi. Total 42 clinical specimens were used to evaluate the ability of this assay for Leishmania species identification. The phylogenetic tree was constructed using HGPRT and SPDSYN gene fragments to validate the performance of this assay. Results This new method was able to detect 3 and 12 parasites/reaction for VL and CL respectively, and exhibited no cross-reaction with P. falciparum, T. gondii, B. melitensis, O. tsutsugamushi and non-target species of Leishmania. Twenty-two samples from VL patients were identified as L. donovani (n = 3) and L. infantum (n = 19), and 20 specimens from CL patients were identified as L. major (n = 20), providing an agreement of 100% compared with sequencing results. For further validation, 29 sequences of HGPRT fragment from nine Leishmania species and 22 sequences from VL patients were used for phylogenetic analysis, which agreed with the results of this new method. Similar results were obtained with 43 sequences of SPDSYN fragment from 18 Leishmania species and 20 sequences from CL patients. Conclusions Our assay provides a rapid and accurate tool for Leishmania species identification which is applicable for species-adapted therapeutic schedule and patient management. Graphical Abstract

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

Cited by 20 publications

References 44 publications

Structural derivatization strategies of natural phenols by semi-synthesis and total-synthesis

Structural derivatization strategies of natural phenols by semi-synthesis and total-synthesis

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

Establish an allele-specific real-time PCR for Leishmania species identification

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