Synthesis and Evaluation of α-Thymidine Analogues as Novel Antimalarials

Cui, Huaqing; Carrero-Lérida, Juana; Silva, Ana P. G.; Whittingham, J.L.; Brannigan, J.A.; Ruíz-Pérez, Luis M.; Read, Kevin D.; Wilson, K.S.; González-Pacanowska, Dolores; Gilbert, Ian H.

doi:10.1021/jm301328h

Cited by 36 publications

(51 citation statements)

References 29 publications

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“…The SYBR Green protocol was used as a confirmatory counter-assay in a 96-well plate format [ 25 ]. This assay quantifies DNA (number of parasites) and thus allows to disregard extracts that interfere or are inhibitors in the LDH assay.…”

Section: Resultsmentioning

confidence: 99%

Discovery of New Compounds Active against Plasmodium falciparum by High Throughput Screening of Microbial Natural Products

et al. 2016

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Due to the low structural diversity within the set of antimalarial drugs currently available in the clinic and the increasing number of cases of resistance, there is an urgent need to find new compounds with novel modes of action to treat the disease. Microbial natural products are characterized by their large diversity provided in terms of the chemical complexity of the compounds and the novelty of structures. Microbial natural products extracts have been underexplored in the search for new antiparasitic drugs and even more so in the discovery of new antimalarials. Our objective was to find new druggable natural products with antimalarial properties from the MEDINA natural products collection, one of the largest natural product libraries harboring more than 130,000 microbial extracts. In this work, we describe the optimization process and the results of a phenotypic high throughput screen (HTS) based on measurements of Plasmodium lactate dehydrogenase. A subset of more than 20,000 extracts from the MEDINA microbial products collection has been explored, leading to the discovery of 3 new compounds with antimalarial activity. In addition, we report on the novel antiplasmodial activity of 4 previously described natural products.

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Section: Resultsmentioning

confidence: 99%

Discovery of New Compounds Active against Plasmodium falciparum by High Throughput Screening of Microbial Natural Products

et al. 2016

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“…The active site architecture of Pf TMPK and human TMPK are highly conserved, but key differences in the Ploop (substrate recognition) and LID domains (active-site cover) suggest that selective compounds could be designed [112]. Cui et al [114] investigated selective inhibitors of the Mycobacterium tuberculosis TMPK [115] for activity against Pf TMPK, and found that α-thymidine analogues ( Figure 2) show moderate activity and weak growth inhibition of cultured P. falciparum. Subsequent crystal structures of Pf TMPK in complex with inhibitors demonstrated that the thymidine ring mimics that of the TMP substrate, the deoxyribose ring acts to orient the thymidine into an enclosed region of the pocket, and bound water molecules illustrate potential regions to target in compound elaboration [113].…”

Section: Tmpk (Thymidylate Kinase)mentioning

confidence: 99%

From crystal to compound: structure-based antimalarial drug discovery

Drinkwater

McGowan

2014

Biochemical Journal

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Despite a century of control and eradication campaigns, malaria remains one of the world's most devastating diseases. Our once-powerful therapeutic weapons are losing the war against the Plasmodium parasite, whose ability to rapidly develop and spread drug resistance hamper past and present malaria-control efforts. Finding new and effective treatments for malaria is now a top global health priority, fuelling an increase in funding and promoting open-source collaborations between researchers and pharmaceutical consortia around the world. The result of this is rapid advances in drug discovery approaches and technologies, with three major methods for antimalarial drug development emerging: (i) chemistry-based, (ii) target-based, and (iii) cell-based. Common to all three of these approaches is the unique ability of structural biology to inform and accelerate drug development. Where possible, SBDD (structure-based drug discovery) is a foundation for antimalarial drug development programmes, and has been invaluable to the development of a number of current pre-clinical and clinical candidates. However, as we expand our understanding of the malarial life cycle and mechanisms of resistance development, SBDD as a field must continue to evolve in order to develop compounds that adhere to the ideal characteristics for novel antimalarial therapeutics and to avoid high attrition rates pre- and post-clinic. In the present review, we aim to examine the contribution that SBDD has made to current antimalarial drug development efforts, covering hit discovery to lead optimization and prevention of parasite resistance. Finally, the potential for structural biology, particularly high-throughput structural genomics programmes, to identify future targets for drug discovery are discussed.

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“…For eukaryotic parasites, most of the inhibitor studies have been conducted against Plasmodium falciparum TMK (PfTMK). Carbocyclic nucleoside analogues, modified thymine base analogues and thymidine urea derivatives have been tested for inhibitory effect on PfTMK (Kato et al, 2012;Kandeel et al, 2009;Cui et al, 2012). In case of prokaryotic TMKs various compounds such as modified thymine base, 3 substituted nucleosides and nucleotides, 2 ,3 bicyclic analogues, thymidine 5 -O-monophosphate analogues, substituted benzyl thymine analogues and acyclic nucleoside analogues were tested against Mycobacterium tuberculosis Vanheusden et al, 2002Vanheusden et al, , 2003Vanheusden et al, 2004;Van Daele et al, 2006;Gasse et al, 2007;Familiar et al, 2008).…”

Section: Introductionmentioning

confidence: 99%