1-(Piperidin-3-yl)thymine amides as inhibitors of <i>M. tuberculosis</i> thymidylate kinase

Jian, Yanlin; Risseeuw, Martijn; Froeyen, Mathy; Song, Lijun; Cappoen, Davie; Cos, Paul; Munier‐Lehmann, Hélène; Calenbergh, Serge Van

doi:10.1080/14756366.2019.1662790

Cited by 10 publications

(9 citation statements)

References 27 publications

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“…Yet, the additional catechol ester of 18 protrudes outward the active site and may form hydrogen bonds with Asp9, Lys13 and Arg95, thereby stabilizing a bent conformation and resulting in an improved inhibitory activity. In line with earlier observations for other piperidine amide analogues [11,43], amide 23 showed very poor inhibitory potency. However, the insertion of a phenylmethylene group between the piperidyl and amide group as in 26 resulted in a 19-fold better potency.…”

Section: Enzyme Inhibitionsupporting

confidence: 90%

Endeavors towards transformation of M. tuberculosis thymidylate kinase (MtbTMPK) inhibitors into potential antimycobacterial agents

Jian

Merceron

Munck

et al. 2020

European Journal of Medicinal Chemistry

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As the last enzyme in nucleotide synthesis as precursors for DNA replication, thymidylate kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.

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Section: Enzyme Inhibitionsupporting

confidence: 90%

Endeavors towards transformation of M. tuberculosis thymidylate kinase (MtbTMPK) inhibitors into potential antimycobacterial agents

Jian

Merceron

Munck

et al. 2020

European Journal of Medicinal Chemistry

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“…(racemic compound 23) resulted in a substantial (> 10-fold) loss in the inhibitory potency. In-line with earlier observations, with a one-carbon linker [14,21], amide analog 26 displayed a weak enzyme inhibition. Having established that 1-(1-arylethylpiperidin-4-yl)thymine is preferable for inhibitory potency, our efforts were then directed toward the exploration of the biphenyl ether tail.…”

Section: Biological Activitysupporting

confidence: 90%

“…Additionally, repositioning of the thymine ring from the para to the meta-position of the piperidine ring [20,22] (racemic compound 23) resulted in a substantial (>10-fold) loss in the inhibitory potency. In-line with earlier observations, with a one-carbon linker [14,21], amide analog 26 displayed a weak enzyme inhibition. (racemic compound 23) resulted in a substantial (> 10-fold) loss in the inhibitory potency.…”

Section: Biological Activitysupporting

confidence: 90%

“…Thymidylate kinase, a key enzyme for the synthesis of the DNA building block thymidine-5′-triphosphate, is indispensable for bacterial survival [ 9 , 10 , 11 ]. The availability of co-crystal structures of Mtb TMPK [ 12 , 13 , 14 , 15 , 16 ] has aided the discovery of Mtb TMPK inhibitors, featuring both nucleoside [ 14 , 17 , 18 , 19 , 20 ] and non-nucleoside [ 14 , 15 , 20 , 21 ] structures.…”

Section: Introductionmentioning

confidence: 99%

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1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors

et al. 2020

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A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold of 3 failed to afford substantial improvements in MtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of 3 resulted in compound 21j with improved MtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of 21j to the para-position afforded isomer 21h, which, despite a 10-fold increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 μM).

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“…Currently, TMK inhibitors are mainly evaluated for their use against Mycobacterium tuberculosis infections (Jian et al . 2019 , 2020 ; Venugopala et al . 2020 ).…”

Section: Introductionmentioning

confidence: 99%

The search for novel treatment strategies forStreptococcus pneumoniaeinfections

Cools

Delputte

Cos

2021

FEMS Microbiology Reviews

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This review provides an overview of the most important novel treatment strategies against Streptococcus pneumoniae infections published over the past 10 years. The pneumococcus causes the majority of community-acquired bacterial pneumonia cases, and it is one of the prime pathogens in bacterial meningitis. Over the last 10 years, extensive research has been conducted to prevent severe pneumococcal infections, with a major focus on (i) boosting the host immune system and (ii) discovering novel antibacterials. Boosting the immune system can be done in two ways, either by actively modulating host immunity, mostly through administration of selective antibodies, or by interfering with pneumococcal virulence factors, thereby supporting the host immune system to effectively overcome an infection. While several of such experimental therapies are promising, few have evolved to clinical trials. The discovery of novel antibacterials is hampered by the high research and development costs versus the relatively low revenues for the pharmaceutical industry. Nevertheless, novel enzymatic assays and target-based drug design, allow the identification of targets and the development of novel molecules to effectively treat this life-threatening pathogen.

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1-(Piperidin-3-yl)thymine amides as inhibitors of M. tuberculosis thymidylate kinase

Cited by 10 publications

References 27 publications

Endeavors towards transformation of M. tuberculosis thymidylate kinase (MtbTMPK) inhibitors into potential antimycobacterial agents

Endeavors towards transformation of M. tuberculosis thymidylate kinase (MtbTMPK) inhibitors into potential antimycobacterial agents

1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors

The search for novel treatment strategies forStreptococcus pneumoniaeinfections

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