The Phthaleins from Phenol and 1,2-Naphthalenedicarboxylic Acid

Hubacher, Max H.

doi:10.1021/ja01230a029

Cited by 5 publications

(3 citation statements)

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“…An alternative pathway was therefore devised by adapting the procedure of Hubacher. 28 As shown in Scheme 4, the 1,8-naphthalic anhydride was heated at 130-140 °C with the appropriate phenol and aluminum chloride for 3 days. The still hot mixture was then poured onto ice and extracted with dichloromethane.…”

Section: Chemistrymentioning

confidence: 99%

Phthalein Derivatives as a New Tool for Selectivity in Thymidylate Synthase Inhibition

Costi¹,

Rinaldi²,

Tondi³

et al. 1999

J. Med. Chem.

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A new set of phthalein derivatives stemming from the lead compound, phenolphthalein, were designed to specifically complement structural features of a bacterial form of thymidylate synthase (Lactobacillus casei, LcTS) versus the human TS (hTS) enzyme. The new compounds were screened for their activity and their specificity against TS enzymes from different species, namely, L. casei (LcTS), Pneumocystis carinii (PcTS), Cryptococcus neoformans (CnTS), and human thymidylate synthase (hTS). Apparent inhibition constants (Ki) for all the compounds against LcTS were determined, and inhibition factors (IF, ratio between the initial rates of the enzymatic reaction in the presence and absence of each inhibitor) against each of the four TS species were measured. A strong correlation was found between the two activity parameters, IF and Ki, and therefore the simpler IF was used as a screening factor in order to accelerate biological evaluation. Compounds 5b, 5c, 5ba, and 6bc showed substantial inhibition of LcTS while remaining largely inactive against hTS, illustrating for the first time remarkable species specificity among TSs. Due to sequence homology between the enzymes, several compounds also showed high activity and specificity for CnTS. In particular, 3-hydroxy-3-(3-chloro-4-hydroxyphenyl)-6-nitro-1H, 3H-naphtho[1,8-c,d]pyran-1-one (6bc) showed an IF < 0.04 for CnTS (Ki = 0.45 microM) while remaining inactive in the hTS assay at the maximum solubility concentration of the compound (200 microM). In cell culture assays most of the compounds were found to be noncytotoxic to human cell lines but were cytotoxic against several species of Gram-positive bacteria. These results are consistent with the enzymatic assays. Intriguingly, several compounds also had selective activity against Cr. neoformans in cell culture assay. In general, the most active and selective compounds against the Gram-positive bacteria were those designed and found in the enzyme assay to be specific for LcTS versus hTS. The original lead compound was least selective against most of the cell lines tested. To our knowledge these compounds are the first TS inhibitors selective for bacterial TS with respect to hTS.

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Section: Chemistrymentioning

confidence: 99%

Phthalein Derivatives as a New Tool for Selectivity in Thymidylate Synthase Inhibition

Costi¹,

Rinaldi²,

Tondi³

et al. 1999

J. Med. Chem.

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“…The compounds were obtained by condensing the 1,2-naphthalic anhydride and phenol according to a known procedure. 20 Separation was accomplished by flash chromatography, eluting with dichloromethane/methanol, 98/2. For 1, the yield was 15%.…”

Section: Methodsmentioning

confidence: 99%

“…Synthesis of 1,1-Bis(4-hydroxyphenyl)-1 H -naphtho[1,2- c ]furan-3-one (1) and 3,3-Bis(4-hydroxyphenyl)-3 H -naphtho[1,2- c ] furan-1-one (2). The compounds were obtained by condensing the 1,2-naphthalic anhydride and phenol according to a known procedure . Separation was accomplished by flash chromatography, eluting with dichloromethane/methanol, 98/2.…”

Section: Methodsmentioning

confidence: 99%

Antibacterial Agent Discovery Using Thymidylate Synthase Biolibrary Screening

et al. 2006

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Thymidylate synthase (TS, ThyA) catalyzes the reductive methylation of 2'-deoxyuridine 5'-monophosphate to 2'-deoxythymidine 5'-monophosphate, an essential precursor for DNA synthesis. A specific inhibition of this enzyme induces bacterial cell death. As a second round lead optimization design, new 1,2-naphthalein derivatives have been synthesized and tested against a TS-based biolibrary, including human thymidylate synthase (hTS). Docking studies have been performed to rationalize the experimentally observed affinity profiles of 1,2-naphthalein compounds toward Lactobacillus casei TS and hTS. The best TS inhibitors have been tested against a number of clinical isolates of Gram-positive-resistant bacterial strains. Compound 3,3-bis(3,5-dibromo-4-hydroxyphenyl)-1H,3H-naphtho[1,2-c]furan-1-one (5) showed significant antibacterial activity, no in vitro toxicity, and dose-response effects against Staphylococcus epidermidis (MIC=0.5-2.5 microg/mL) clinical isolate strains, which are resistant to at least 17 of the best known antibacterial agents, including vancomycin. So far this compound can be regarded as a leading antibacterial agent.

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