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| {{OpenSourceTB}} | | {{OpenSourceTB}} |
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| ==Starting Point==
| | Coming shortly |
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| TCMDC143693 identified by GSK in a high throughput screen (to be published shortly).
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| [[Image:GSK2290170A.png|thumb|center|250px|TCMDC143693, the Starting Point for OSTB Series 2]]
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| ===Properties===
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| Inherited data from GSK for TCMDC-143693: MIC ''vs.'' H37Rv = 10 μM, active against non-replicating TB (>50% inhibition) in 10 experiments out of 13) and with mean PXC<sub>50</sub> of 5.2 μM. Toxicity ''vs.'' HepG2 was >100 μM. cLogP is 3.1 and (presumably) measured solubility is 72 μg/mL. Chrom LogD (pH 7.4) is 5.21, and molecular weight 385.
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| ===Known occurrences===
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| TCMDC143693 was, when this page was created, absent from Google.
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| Pubchem search leads to a [https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2009176778 patent].
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| ChEMBL flags up that a search on SureChEMBL reveals that the compound has appeared (along with nearest neighbours) on 2 patents of the same patent family: https://www.surechembl.org/document/US-20090176778-A1/ and https://www.surechembl.org/document/US-20120121540-A1/
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| ===Related Structures===
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| [http://www.nature.com/nm/journal/v19/n9/full/nm.3262.html Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis]<br>
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| [http://pubs.acs.org/doi/abs/10.1021/jm5003606 Lead Optimization of a Novel Series of Imidazo(1,2-a)pyridine Amides Leading to a Clinical Candidate (Q203) as a Multi- and Extensively-Drug-Resistant Anti-tuberculosis Agent]<br>
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| [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0052951 Identification of Novel Imidazo(1,2-a)pyridine Inhibitors Targeting M. tuberculosis QcrB]<br>
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| [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087483 Bactericidal Activity of an Imidazo(1, 2-a)pyridine Using a Mouse M. tuberculosis Infection Model]<br>
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| [http://pubs.acs.org/doi/abs/10.1021/id500008t Putting Tuberculosis (TB) To Rest: Transformation of the Sleep Aid, Ambien, and “Anagrams” Generated Potent Antituberculosis Agents]
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| ===Predicted Target===
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| A prediction of the target was carried out by [http://www.crg.eu/en/programmes-groups/structural-genomics Marc Marti-Renom] and [https://www.ebi.ac.uk/chembl/ ChEMBL] as part of the original HTS paper identifying the compound.
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| The compound (TCMDC143693) has four predictions, three from Marc's approach and one from the ChEMBL’s approach. (The details on how the predictions were identified are in the forthcoming manuscript).
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| Marc's predictions:<br>
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| 1) O06266 (an epoxide hydrolase). Link: TCMDC143693 —> 3TH-S38-3ans_A —> S38-O06266 (i.e. the GSK compound is similar to 3TH in PDB, which was co-crystallized with 3ans (a Human soluble epoxide hydrolase in complex with a synthetic inhibitor). In turn, the model of the Tuberculosis epoxide hydrolase (O06266) was based on 3ans template and the binding site was conserved. Thus, the path links TCMDC143693 to O06266.<br>
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| 2) A2VJ47 (an epoxide hydrolase ephB), TCMDC143693 —> 3TH-S38-3ans_A —> S38-A2VJ47 <br>
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| 3) P64411 (Heat shock protein 90, TCMDC143693 —> 3TH-PFT-3k99_A —> PFT-P64411 <br>
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| The EBI prediction:<br>
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| P96222 (Mtb HTH-type transcriptional regulator Eth) now http://www.uniprot.org/uniprot/P9WMC1 and https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL1772929. The compound shares a lot of structural features found in known actives (activity <=10 μM) for this target in ChEMBL. These features include the thiophene ring, -CF<sub>3</sub>, pyrrole ring and nitrile.
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| Current question: are there known inhibitors of any of these targets that show inhibition of Mtb? There is a [http://pubs.acs.org/doi/abs/10.1021/jm500422b paper] identifying hits ''vs.'' this target, but the effect of inhibition is to increase the potency of another compound - the compounds are not themselves antitubercular. Thus if TCMDC143693 has potency on its own (which it does), perhaps there is another (different or additional) MoA.
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| ===Synthetic Chemistry===
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| Our initial efforts to explore the series were focused on the resynthesis of our hit compound TCMDC-143693. The synthesis of this compound has been already described ( https://www.surechembl.org/document/US-20120121540-A1/), therefore the same sequence of reactions was performed. The synthesis started with bromination at the 5-position of the 2-amino-3-(trifluoromethyl) pyridine ([https://au-mynotebook.labarchives.com/share/Jessica%2520Baiget%2520Gonzalez/ODUuOHw2NTUvNjYvVHJlZU5vZGUvMjE3NzMwMzA3OHwyMTcuOA== JBG28-1]) followed by cyclisation with ethyl bromopyruvate to generate the imidazopyridine ring ([https://au-mynotebook.labarchives.com/share/Jessica%2520Baiget%2520Gonzalez/MTE1Ljd8NjU1Lzg5L1RyZWVOb2RlLzM2MTc2OTk3MjR8MjkzLjc= JBG43-1]), which was chlorinated at the 3-position with N-chlorosuccinimide ([https://au-mynotebook.labarchives.com/share/Jessica%2520Baiget%2520Gonzalez/MTE4LjN8NjU1LzkxL1RyZWVOb2RlLzIxMTc0MTE3NjZ8MzAwLjM= JBG45-1]). The resulting ester was hydrolysed with NaOH ([https://au-mynotebook.labarchives.com/share/Jessica%2520Baiget%2520Gonzalez/MTIyLjJ8NjU1Lzk0L1RyZWVOb2RlLzEyMjE5MzA1ODl8MzEwLjI= JBG47-1]) to generate the corresponding acid, which could easily be converted to the amide by treatment with 2-(aminomethyl)thiophene and a coupling agent such as T3P ([https://au-mynotebook.labarchives.com/share/Jessica%2520Baiget%2520Gonzalez/MTIzLjV8NjU1Lzk1L1RyZWVOb2RlLzM0NDcxMzE2NzJ8MzEzLjU= JBG48-1]). The last step, the palladium cyanylation reaction, was modified from the procedure described in the literature, with a longer reaction time and conventional heating instead of microwave irradiation improving the yield of the final compound ([https://au-mynotebook.labarchives.com/share/Jessica%2520Baiget%2520Gonzalez/MTI2LjF8NjU1Lzk3L1RyZWVOb2RlLzQyNjE1NzcyMDR8MzIwLjE= JBG50-1]).
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| [[Image:Synthesis of TCMDC-143693.png|thumb|center|900px|Synthesis of TCMDC143693]]
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| ==Strings==
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| '''TCMDC143693''' ClC1=C(C(NCC2=CC=CS2)=O)N=C3C(C(F)(F)F)=CC(C#N)=CN31 InChI=1S/C15H8ClF3N4OS/c16-12-11(14(24)21-6-9-2-1-3-25-9)22-13-10(15(17,18)19)4-8(5-20)7-23(12)13/h1-4,7H,6H2,(H,21,24) LWIBMEYBVJUXDE-UHFFFAOYSA-N <br>
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| ==Licence==
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| Content is [https://creativecommons.org/licenses/by/4.0/ CC-BY-4.0].
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| ==Contact==
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| To discuss this project or page, see the contact info on the [[OpenSourceTB |'''OSTB Main Page''']]
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