4-Hydroxy-2-quinolones. 32. Synthesis and antithyroid activity of thio analogs of 1H-2-oxo-3-(2-Benzimidazolyl)-4-hydroxyquinoline

Abstract

We propose preparative synthesis methods for 2-thio-4-hydroxy-, 2-oxo-4-mercapto-, and 2 ~thio-4-mercapto-l H-3-(2-benzimidazolyl)quinolines. We have studied the antithyroid activity of the synthesized compounds.As we know, the basis for the arsenal of the most effective modern drugs for treatment of thyrotoxicosis is provided by thio(mercapto) derivatives of some heterocycles: uracil, barbituric acid, imidazole, triazole, thiazole, and others [2].Earlier we noted the high antithyroid activity of 1-R-2-oxo-3-(2-benzimidazolyl)-4-hydroxyquinolines [3], the most promising of which proved to be the 1H derivative I [4], having greater specific activity and toxicity than the drug mercazolyl used in medical practice.This investigation was devoted to synthesis and study of the antithyroid properties of thio analogs of quinolone I. 2-Thio-4-mercapto-(II) and 2-oxo-4-mercapto-(HI) 1H-3-(2-benzimidazolyl) quinolines were obtained by the simple scheme of treatment of ethyl esters of respectively 2,4-dichloro (IV) and 2-oxo-4-chloro-(V) quinoline-3-carboxylic acids with thiourea in acetone. Base hydrolysis of the thiouronium salts VI and VII formed in this case yields thio-substituted 3-carbethoxyquinolines VIII and IX (it is interesting that the ester groups are not involved here), thermolysis of which with an equimolar amount of o-phenylenedi~mine leads to the target benzimidazolylquinolones H and HI.The synthesis of 1H-2-thio-3-(2-benzimidazolyl)-4-hydroxyquinoline (X) seems somewhat more complicated, in our opinion, especially due to the tendency of 2-and 4-hydroxyquinoline-3-carboxyl acids toward facile decarboxylation under thermolysis conditions [5, 6], which predetermines the need for esterification of the starting 2-chloro-4-hydroxyquinoline-3-carboxylic acid in this case [7]. However, we unexpectedly found a rather simple solution to this problem. MMX calculations for quinolone I show that the most energetically favorable arrangement for it is the arrangement of the quinolone and benzimidazole heterocyclic systems in the same plane, stabilized by two intramolecular hydrogen bonds. Evidence for the presence of strong intramolecular hydrogen bonds also comes from the singlet signals of 2H intensity from the protons of the 4-OH groups of the quinolone and the NH groups of the benzimidazole in the PMR spectra of these compounds [3, 8] and in addition the extremely low solubility of quinolone I and its 1-alkyl analogs in aqueous bases. If there are differences between the strength of the intramolecular hydrogen bonds, this fact allows us to suggest the possibility of obtaining reactions of quinolone I with the phosphorus oxychloride of the monochloro-substituted derivative. In fact, for relatively brief heating of quinolone I in POC13, the monochioro-substituted quinoline is formed according to the mass spectrum. In order to unambiguously resolve the question of its structure, we synthesized a compound with known 2-oxo-4-chloroquinoline structure XII. Comparison of the electronic absorption spectra of these compounds (...

Solid-Phase Synthesis of Quinolinone Library

“…A large number of pharmacologically active molecules have been generated by synthesizing derivatives of quinolinone. Many of these compounds have potent and varied biological activities including antibacterial, , anticonvulsant, , and antithyroid − properties. In addition, amide derivatives of substituted 2-oxo-quinoline acids have shown anticancer − and antituberculosis − activities.…”

“…1923.N-(4-Chlorophenethyl)-5-(2-(3-chlorophenoxy)acetamido)-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (21{2,6}).1 H NMR (400 MHz, CDCl 3 ): δ 9.91 (s, 1H), 9.12 (s, 1H), 8.78 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.20− 7.16 (m, 2H), 7.12−7.04 (m, 5H), 7.02−6.98 (m, 2H),6.84 (d, J = 12.0 Hz, 2H), 5.54 (s, 2H), 4.72 (s, 1H), 3.76 (s, 3H), 3.71−3.66 (m, 2H), 2.95−2.85 (m, 2H), 1.32−1.23 (m, 2H). MS(ESI) m/z: 629.66 ([M + H] + ).…”

Synthesis and Characterization of Substituted 4‐Methoxy‐1H‐quinolin‐2‐ones

“…Heterocyclic compounds have different types of pharmacological properties [1][2] . Several quinolones like ciprofloxacin, pefloxacin, levofloxacin, spafloxacin are released in the clinical world.…”

4-hydroxy-2-quinolones. 191.* synthesis, tautomerism and biological activity of benzimidazol-2-ylamides of 1-r-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids

“…The present drugs have serious side effects and, as a consequence, many contraindications for practical application [9][10][11][12][13][14][15]. For this reason, the search for new safe drugs suitable for treating hyperthyroidotoxicosis holds considerable importance today.Compounds with high antithyroid activity, low toxicity, and no goiter-inducing effect were discovered in a study of the biological properties of 3-(benzimidazol-2-yl)-4-hydroxy-2-oxo-1,2-dihydroquinolines [16] and then their many structural analogs [17][18][19][20]. As a result, a new drug has been developed on the basis of one of them for treating diseases related to overproduction of thyroid hormones [21].…”

“…Compounds with high antithyroid activity, low toxicity, and no goiter-inducing effect were discovered in a study of the biological properties of 3-(benzimidazol-2-yl)-4-hydroxy-2-oxo-1,2-dihydroquinolines [16] and then their many structural analogs [17][18][19][20]. As a result, a new drug has been developed on the basis of one of them for treating diseases related to overproduction of thyroid hormones [21].…”