Synthesis and biological activity of hydrochlorides of benzyl ethers of pyrimidin-4(3H)-thiones and related compounds

Erkin, A. V.; Gurzhii, V. V.; Krutikov, V. I.

doi:10.1134/s1070363215010144

“…Hydroxypyrimidines 151 and 152 were readily separated by silica gel flash chromatography (Rf = 0.37 and 0.53, CH2Cl2/MeOH/EtOH/NH3 (25%), 5/2/2/1 v/v/v/v, respectively) before they were treated with POCl3 to give the desired chloropyrimidines, 153 and 154, respectively. The spectral data obtained for pyrimidines 150279 and 153285 matched those reported in the literature, while the formation of chloride 154 was evidenced by NMR spectroscopy and HRMS data (calcd. for [C6H8ClN3O+H] + : 174.0429, obsd.…”

supporting

confidence: 80%

“…Chloropyrimidines XVII could, in turn, be prepared by the condensation of functionalised beta-ketoesters 147 with guanidine, followed by a chlorination reaction. 279 Substituted chromones XVIII could be constructed from the condensation of 2'-hydroxyacetophenone (123) with functionalised acid chlorides or carboxylic acids to form an ester, which would then undergo an acid-catalysed cyclisation reaction. 280 The library of functionalised chromonylpyrimidines (XVI) will then be screened for their ability to inhibit Mtb.…”

Section: Project Aims and Retrosynthesismentioning

confidence: 99%

The Synthesis and Evaluation of Heterocycles as Anti-Tuberculosis Agents

Santoso¹

0

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<p>Tuberculosis (TB) is the leading cause of death from a single infectious agent, Mycobacterium tuberculosis (Mtb), worldwide. Currently, the efficacy of TB treatment regimens has declined due to the rise in antibacterial resistance and the shortage of new TB drugs. Thus, much effort has been spent in anti-tuberculosis drug development and in identifying new therapeutic targets against Mtb. One such target is NADH dehydrogenase-II (NDH-II), an essential enzyme in the mycobacterial electron transport chain that is not present in mammalian cells. In this thesis, four classes of heterocyclic compounds that have the potential to target NDH-II and their evaluation as anti-tubercular agents, are described. An overview of TB drug development and NDH-II as a promising target for TB drugs are described in Chapter 1. In Chapters 2 and 3, the potential of anti-tubercular drugs based on the quinolinequinone (QQ) scaffold is described. QQs have previously shown promise as TB drugs by activating NDH-II to overproduce harmful reactive oxygen species leading to bacterial cell death. Chapter 2 describes the total synthesis of the QQ natural products ascidiathiazone A and ascidiathiazone B, and derivatives thereof, using a synthetic route that allows for high divergency and the efficient synthesis of the natural products and their intermediates. To this end, the first total synthesis of ascidiathiazone B is reported, as is the identification of ascidiathiazone A as a promising anti-tuberculosis drug with an MIC of 1.6 μM against Mtb. Insight into the ability of a representative quinone, 7-chloro-6-chloroethylamino-2-methyl-QQ, to increase NDH-II activity is also described. In Chapter 3, the syntheses of thirty-two simplified QQs with different functional groups at the 6- and 7-positions of the QQ scaffold are described. These compounds were screened against Mtb, with the lead compound from this library, 7-chloro-6-propargylamino-QQ, exhibiting an MIC of 8 μM against Mtb. Structure-activity data revealed diminished biological activity for QQs bearing tertiary amines, as compared to those with secondary amines, suggesting that the presence of a hydrogen bond donor at the 6- and 7-positions of QQs may play a critical role in antimycobacterial activity. In Chapter 4, the synthesis and anti-mycobacterial activity of chromonyl-pyrimidines is presented. Chromonyl-pyrimidines have a structural resemblance to quinolinyl pyrimidines, a class of known NDH-II inhibitors and anti-TB agents. Chromones have shown promise as TB drugs, though they have not yet been reported to bind NDH-II. Despite this, chromonyl-pyrimidines contain a ketone functionality that may be able to bind the quinone binding site. For the first eleven-member library of chromonyl pyrimidines synthesised, all but two of the compounds exhibited inhibitory activity against Mtb, however, the growth inhibition was modest (MIC = 36-684 M). Accordingly, a second generation of chromonyl pyrimidines was synthesised, which included six compounds with improved potency against Mtb – all with an MIC value of 12.5 μM. The activity of these chromonyl pyrimidines was attributed to the presence of aromatic rings both on the pyrimidine and the chromone scaffolds, though changes to the electronic properties of the aryl groups, i.e. the incorporations of electron-withdrawing and electron-donating groups, did not affect inhibitory activity. Finally, in Chapter 5, a library of phthalazinones and pyrimidinyl-phthalazinones with anti-tubercular activity is described. While phthalazinones have not yet been extensively explored as anti-mycobacterial agents, the phthalazinone scaffold has the potential to act as an uncoupler. Uncouplers are typically weak acids or bases that act on the electron transport chain by dissipating the proton motive force and ultimately preventing the generation of ATP. In Mtb, this uncoupling process is detrimental and leads to cell death. Phthalazinones are weakly basic and, due to their bicyclic ketone-bearing motif, has the potential to bind NDH-II at the proposed Q-site. Accordingly, a series of phthalazinones was synthesised to investigate their anti-tubercular activity and uncoupling activity. From the library of phthalazinones, N-tert-butyl- and nitro-substituted phthalazinones elicited high inhibitory activity, both with an MIC value of 3 μM. Of particular note among the pyrimidinyl-phthalazinones was the 4-fluorophenyl-pyrimidinyl-N-heptyl phthalazinone, which showed high potency against Mtb with an MIC of 1.6 μM. Further biological studies showed that some phthalazinones increased the rate of NADH oxidation in mycobacteria, which could be a result of uncoupling activity, while a number of pyrimidinyl-phthalazinones decreased NADH oxidation rates. These mechanistic results indicated that the two classes of compounds may have different modes of inhibition.</p>

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“…Pyrimidines installed with methyl, chloromethyl, and methoxymethyl groups would provide insight into how the electronic properties of the pyrimidine ring influence the antimycobacterial activity of the compounds, while substituents at the 2‐position, such as ester, cyclopropyl and phenyl groups, can be incorporated to probe the importance hydrophobic residues at this position. Chloro‐pyrimidines III were, in turn, proposed to be prepared via the condensation of functionalised β‐ketoesters V with guanidine, followed by a chlorination reaction, while chromones IV could be constructed by the esterification of 2′‐hydroxyacetophenone with functionalised acid chlorides or carboxylic acids, which would then undergo an acid‐catalysed annulation …”

Section: Resultsmentioning

confidence: 99%

“…With the retrosynthetic plan in place, chloro‐pyrimidines III were prepared by condensing guanidine hydrochloride ( 3 ) with ethyl acetoacetate in the presence of sodium hydride to give pyrimidinol 4 (Scheme ) . Pyrimidinol 4 was then treated with POCl 3 to give 4‐chloro‐6‐methylpyrimidine ( 5 ) . In an analogous manner, guanidine hydrochloride 3 was treated with ethyl 4‐chloroacetoacetate to give hydroxymethyl‐ ( 6 ) and methoxymethyl‐ ( 7 ) pyrimidines in approximately 2 : 1 ratio and a combined yield of 83%.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Functionalised Chromonyl‐pyrimidines and Their Potential as Antimycobacterial Agents

Santoso

¹

,

Brett

²

,

Cheung

³

et al. 2020

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Drug-resistant strains of Mycobacterium tuberculosis are on the rise and have resulted in an urgent need to develop new tuberculosis (TB) drugs. Herein, the development of chromonylpyrimidines as a new TB drug scaffold is presented. A library of eleven chromonyl-pyrimidines was synthesised, from which lead compound 6-((2-amino-6-methylpyrimidin-4-yl)amino)-3benzoyl-2-phenyl-4H-chromen-4-one (MIC = 36 μM against M. tuberculosis) was identified. A second-generation library of seven aryl-substituted chromonyl-pyrimidines was then prepared, with six chromonyl-pyrimidines exhibiting an improved M. tuberculosis growth inhibition (MIC = 12.5 μM). From this work, the potential of chromonyl-pyrimidines as therapeutics for TB is demonstrated.[a] Dr.

show abstract

“…Chloropyrimidines XVII could, in turn, be prepared by the condensation of functionalised beta-ketoesters 147 with guanidine, followed by a chlorination reaction. 279 Substituted chromones XVIII could be constructed from the condensation of 2'-hydroxyacetophenone (123) with functionalised acid chlorides or carboxylic acids to form an ester, which would then undergo an acid-catalysed cyclisation reaction. 280 The library of functionalised chromonylpyrimidines (XVI) will then be screened for their ability to inhibit Mtb.…”

Section: Project Aims and Retrosynthesismentioning

confidence: 99%

The Synthesis and Evaluation of Heterocycles as Anti-Tuberculosis Agents

Santoso¹

0

View full text Add to dashboard Cite

<p>Tuberculosis (TB) is the leading cause of death from a single infectious agent, Mycobacterium tuberculosis (Mtb), worldwide. Currently, the efficacy of TB treatment regimens has declined due to the rise in antibacterial resistance and the shortage of new TB drugs. Thus, much effort has been spent in anti-tuberculosis drug development and in identifying new therapeutic targets against Mtb. One such target is NADH dehydrogenase-II (NDH-II), an essential enzyme in the mycobacterial electron transport chain that is not present in mammalian cells. In this thesis, four classes of heterocyclic compounds that have the potential to target NDH-II and their evaluation as anti-tubercular agents, are described. An overview of TB drug development and NDH-II as a promising target for TB drugs are described in Chapter 1. In Chapters 2 and 3, the potential of anti-tubercular drugs based on the quinolinequinone (QQ) scaffold is described. QQs have previously shown promise as TB drugs by activating NDH-II to overproduce harmful reactive oxygen species leading to bacterial cell death. Chapter 2 describes the total synthesis of the QQ natural products ascidiathiazone A and ascidiathiazone B, and derivatives thereof, using a synthetic route that allows for high divergency and the efficient synthesis of the natural products and their intermediates. To this end, the first total synthesis of ascidiathiazone B is reported, as is the identification of ascidiathiazone A as a promising anti-tuberculosis drug with an MIC of 1.6 μM against Mtb. Insight into the ability of a representative quinone, 7-chloro-6-chloroethylamino-2-methyl-QQ, to increase NDH-II activity is also described. In Chapter 3, the syntheses of thirty-two simplified QQs with different functional groups at the 6- and 7-positions of the QQ scaffold are described. These compounds were screened against Mtb, with the lead compound from this library, 7-chloro-6-propargylamino-QQ, exhibiting an MIC of 8 μM against Mtb. Structure-activity data revealed diminished biological activity for QQs bearing tertiary amines, as compared to those with secondary amines, suggesting that the presence of a hydrogen bond donor at the 6- and 7-positions of QQs may play a critical role in antimycobacterial activity. In Chapter 4, the synthesis and anti-mycobacterial activity of chromonyl-pyrimidines is presented. Chromonyl-pyrimidines have a structural resemblance to quinolinyl pyrimidines, a class of known NDH-II inhibitors and anti-TB agents. Chromones have shown promise as TB drugs, though they have not yet been reported to bind NDH-II. Despite this, chromonyl-pyrimidines contain a ketone functionality that may be able to bind the quinone binding site. For the first eleven-member library of chromonyl pyrimidines synthesised, all but two of the compounds exhibited inhibitory activity against Mtb, however, the growth inhibition was modest (MIC = 36-684 M). Accordingly, a second generation of chromonyl pyrimidines was synthesised, which included six compounds with improved potency against Mtb – all with an MIC value of 12.5 μM. The activity of these chromonyl pyrimidines was attributed to the presence of aromatic rings both on the pyrimidine and the chromone scaffolds, though changes to the electronic properties of the aryl groups, i.e. the incorporations of electron-withdrawing and electron-donating groups, did not affect inhibitory activity. Finally, in Chapter 5, a library of phthalazinones and pyrimidinyl-phthalazinones with anti-tubercular activity is described. While phthalazinones have not yet been extensively explored as anti-mycobacterial agents, the phthalazinone scaffold has the potential to act as an uncoupler. Uncouplers are typically weak acids or bases that act on the electron transport chain by dissipating the proton motive force and ultimately preventing the generation of ATP. In Mtb, this uncoupling process is detrimental and leads to cell death. Phthalazinones are weakly basic and, due to their bicyclic ketone-bearing motif, has the potential to bind NDH-II at the proposed Q-site. Accordingly, a series of phthalazinones was synthesised to investigate their anti-tubercular activity and uncoupling activity. From the library of phthalazinones, N-tert-butyl- and nitro-substituted phthalazinones elicited high inhibitory activity, both with an MIC value of 3 μM. Of particular note among the pyrimidinyl-phthalazinones was the 4-fluorophenyl-pyrimidinyl-N-heptyl phthalazinone, which showed high potency against Mtb with an MIC of 1.6 μM. Further biological studies showed that some phthalazinones increased the rate of NADH oxidation in mycobacteria, which could be a result of uncoupling activity, while a number of pyrimidinyl-phthalazinones decreased NADH oxidation rates. These mechanistic results indicated that the two classes of compounds may have different modes of inhibition.</p>

show abstract

Synthesis and biological activity of hydrochlorides of benzyl ethers of pyrimidin-4(3H)-thiones and related compounds

Cited by 7 publications

References 9 publications

The Synthesis and Evaluation of Heterocycles as Anti-Tuberculosis Agents

The Synthesis and Evaluation of Heterocycles as Anti-Tuberculosis Agents

Synthesis of Functionalised Chromonyl‐pyrimidines and Their Potential as Antimycobacterial Agents

The Synthesis and Evaluation of Heterocycles as Anti-Tuberculosis Agents

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