Synthesis and evaluation of 5′-modified thymidines and 5-hydroxymethyl-2′-deoxyuridines as Mycobacterium tuberculosis thymidylate kinase inhibitors

Toti, Kiran S.; Verbeke, Frederick; Risseeuw, Martijn; Frecer, Vladimı́r; Munier‐Lehmann, Hélène; Calenbergh, Serge Van

doi:10.1016/j.bmc.2012.10.018

Cited by 14 publications

(8 citation statements)

References 24 publications

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“…Flash column chromatography on silica gel (CH2Cl2/MeOH = 100:1) afforded 5-O-TBS desilylated nucleoside in pure form. The characterization data of known compounds (13, 6, 7, 1116) were compared with previous reports [3][4][5][6][7][8][9][10] and are in agreement with literature values. 3 .…”

Section: General Proceduressupporting

confidence: 82%

A Practical Method for Regioselective 5′-O-tert-Butyldimethylsilyl Deprotection of Persilylated Nucleosides by Methanolic Phosphomolybdic Acid

Huang¹,

Kong²,

Zheng³

et al. 2018

Synlett

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In nucleoside/nucleotide chemistry, the regioselective cleavage of 5′-O-TBS groups of persilylated nucleosides is a desired approach for structural functionalization at the 5′-position. However, efficient and practical methods for this purpose are still limited. In our research, we found that homogeneous methanolic phosphomolybdic acid (PMA) efficiently catalyzes the regioselective deprotection of 5′-O-TBS groups of a diversity of persilylated nucleoside substrates and can be applied in practical synthesis at scales of up to 15 g. 31P NMR results indicated that an anion cluster forms and the Lewis acidity of homogeneous PMA is organic-solvent dependent. The efficacy and pronounced regioselectivity of methanolic PMA occurs as a result of a lowering of the Lewis acid strength upon solvation of the molybdophosphate anions.

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Section: General Proceduressupporting

confidence: 82%

A Practical Method for Regioselective 5′-O-tert-Butyldimethylsilyl Deprotection of Persilylated Nucleosides by Methanolic Phosphomolybdic Acid

Huang¹,

Kong²,

Zheng³

et al. 2018

Synlett

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“…This allows for the development of selective inhibitors that target MTB-TMK without affecting healthy human cells. 10 Although most MTB-TMK inhibitors are thymidine monophosphate analogues that contain a nucleoside core, [11][12][13][14][15][16][17] some thymine non-nucleoside derivatives have also been reported to be potent MTB-TMK inhibitors. [18][19][20][21] Two novel classes, 3cyanopyridones and 1.6-naphthyridin-2-ones, were recently identified as MTB-TMK inhibitors via high-throughput screening and structural optimization to improve potency ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

<p>In silico Design and Synthesis of Tetrahydropyrimidinones and Tetrahydropyrimidinethiones as Potential Thymidylate Kinase Inhibitors Exerting Anti-TB Activity Against <em>Mycobacterium tuberculosis</em></p>

Venugopala¹,

Tratrat²,

Pillay³

et al. 2020

DDDT

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Background and Purpose: Tuberculosis has been reported to be the worldwide leading cause of death resulting from a sole infectious agent. The emergence of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has made the battle against the infection more difficult since most currently available therapeutic options are ineffective against these resistant strains. Therefore, novel molecules need to be developed to effectively treat tuberculosis disease. Preliminary docking studies revealed that tetrahydropyrimidinone derivatives have favorable interactions with the thymidylate kinase receptor. In the present investigation, we report the synthesis and the mycobacterial activity of several pyrimidinones and pyrimidinethiones as potential thymidylate kinase inhibitors. Methods: The title compounds (1a-d) and (2a-b) were synthesized by a one-pot three-component Biginelli reaction. They were subsequently characterized and used for whole-cell anti-TB screening against H37Rv and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) by the resazurin microplate assay (REMA) plate method. Molecular modeling was conducted using the Accelry's Discovery Studio 4.0 client program to explain the observed bioactivity of the compounds. The pharmacokinetic properties of the synthesized compounds were predicted and analyzed. Results: Of the compounds tested for anti-TB activity, pyrimidinone 1a and pyrimidinethione 2a displayed moderate activity against susceptible MTB H37Rv strains at 16 and 32 µg/mL, respectively. Only compound 2a was observed to exert modest activity at 128 µg/mL against MTB strains with cross-resistance to rifampicin and isoniazid. The presence of the trifluoromethyl group was essential to retain the inhibitory activity of compounds 1a and 2a. Molecular modeling studies of these compounds against thymidylate kinase targets demonstrated a positive correlation between the bioactivity and structure of the compounds. The in-silico ADME (absorption, distribution, metabolism, and excretion) prediction indicated favorable pharmacokinetic and drug-like properties for most compounds. Conclusion: Pyrimidinone 1a and pyrimidinethione 2a were identified as the leading compounds and can serve as a starting point to develop novel anti-TB therapeutic agents.

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“…About this additional HB with Tyr39 it is interesting to point out, among the few differences of the binding sites of TMPK mt and TMPK h (the human corresponding enzyme-PDB code 1E99) where Arg14, Tyr39 and Asn100 are replaced in the last one by Ser20, Arg45 and Gly102, respectively [41], the crucial opportunity to exploit this structural and functional difference (interaction with Tyr39) to design selective inhibitors for TMPK mt . Recent attempts of extension by replacement of the carboxylate COO − with other groups resulting in 5′-modified thymidines are promising [42]. …”

Section: Resultsmentioning

confidence: 99%

Design of Thymidine Analogues Targeting Thymidilate Kinase ofMycobacterium tuberculosis

Owono

Keita

Megnassan

et al. 2013

Tuberculosis Research and Treatment

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We design here new nanomolar antituberculotics, inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt), by means of structure-based molecular design. 3D models of TMPKmt-inhibitor complexes have been prepared from the crystal structure of TMPKmt cocrystallized with the natural substrate deoxythymidine monophosphate (dTMP) (1GSI) for a training set of 15 thymidine analogues (TMDs) with known activity to prepare a QSAR model of interaction establishing a correlation between the free energy of complexation and the biological activity. Subsequent validation of the predictability of the model has been performed with a 3D QSAR pharmacophore generation. The structural information derived from the model served to design new subnanomolar thymidine analogues. From molecular modeling investigations, the agreement between free energy of complexation (ΔΔG com) and K i values explains 94% of the TMPKmt inhibition (pK i = −0.2924ΔΔG com + 3.234; R 2 = 0.94) by variation of the computed ΔΔG com and 92% for the pharmacophore (PH4) model (pK i = 1.0206 × pK i pred − 0.0832, R 2 = 0.92). The analysis of contributions from active site residues suggested substitution at the 5-position of pyrimidine ring and various groups at the 5′-position of the ribose. The best inhibitor reached a predicted K i of 0.155 nM. The computational approach through the combined use of molecular modeling and PH4 pharmacophore is helpful in targeted drug design, providing valuable information for the synthesis and prediction of activity of novel antituberculotic agents.

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Synthesis and evaluation of 5′-modified thymidines and 5-hydroxymethyl-2′-deoxyuridines as Mycobacterium tuberculosis thymidylate kinase inhibitors

Cited by 14 publications

References 24 publications

A Practical Method for Regioselective 5′-O-tert-Butyldimethylsilyl Deprotection of Persilylated Nucleosides by Methanolic Phosphomolybdic Acid

A Practical Method for Regioselective 5′-O-tert-Butyldimethylsilyl Deprotection of Persilylated Nucleosides by Methanolic Phosphomolybdic Acid

<p>In silico Design and Synthesis of Tetrahydropyrimidinones and Tetrahydropyrimidinethiones as Potential Thymidylate Kinase Inhibitors Exerting Anti-TB Activity Against <em>Mycobacterium tuberculosis</em></p>

Design of Thymidine Analogues Targeting Thymidilate Kinase ofMycobacterium tuberculosis

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