Phenothiazine derivatives and their use in treating pulmonary tuberculosis

A technology of derivatives and uses, applied in medical preparations containing active ingredients, pharmaceutical formulas, organic chemistry, etc., can solve problems such as limiting antibacterial efficacy and adverse central nervous system side effects

Inactive Publication Date: 2018-10-19
UNIVERSITY OF CAPE TOWN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These neuroleptic properties limit the antimicrobial utility of these drugs in diseases such as tuberculosis because they can induce unwanted central nervous system (CNS) side effects at mycobactericidal doses

Method used

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  • Phenothiazine derivatives and their use in treating pulmonary tuberculosis
  • Phenothiazine derivatives and their use in treating pulmonary tuberculosis
  • Phenothiazine derivatives and their use in treating pulmonary tuberculosis

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Experimental program
Comparison scheme
Effect test

Embodiment approach

[0037]

[0038] In a more preferred embodiment, the tricyclic derivative of general formula (1) can be selected from:

[0039]

[0040] The process of preparing N-alkyl sulfonate of phenothiazine includes:

[0041] (a) Preparation of phenothiazine anions, and

[0042] (b) The reaction of the anion with a cycloalkyl sulfonate (e.g. 1,3-propane sultone or 1,4-butane sultone) is roughly described in US Patent 7,855,287.

[0043] An inefficient multi-step synthesis method was earlier disclosed in Journal of Physical Chemistry, 1986, 90, 2469-2415.

[0044] The phenothiazine derivatives of the present invention have been shown to have limited toxicity to primary macrophage cell cultures and limited psychoactive activity.

[0045] It is believed that the anti-schizophrenic activity of phenothiazine drugs is related to the blockage of synaptic dopamine receptors in the brain. It has been shown by molecular space-filling models that the favorable van der Waals interaction between the side chain...

Embodiment

[0057] Phenothiazine derivatives show direct antibacterial activity against Mycobacterium tuberculosis in culture

[0058] The GFAP microplate assay (GFPMA) was used to evaluate the five compounds C3, C4, C31, C32 and C33 (shown below) against Mycobacterium tuberculosis in order to screen for the bactericidal / bacteriostatic activity of phenothiazine derivatives.

[0059]

[0060] The results were compared with the known phenothiazine derivative thioridazine (TZ) and the first line drug isoniazid (INH), which was used as a positive control for anti-mycobacterial efficacy. The results obtained have shown that, except for C33, all test compounds showed a dose-dependent inhibitory effect on the growth of M.tb H37Rv.gfp, and the obtained MICs were summarized 50 value( figure 1 ). MIC of INH and TZ 50 The value is similar to the published data. The significant anti-tuberculosis activity of C3 and C4 was confirmed, which has the lowest MIC, as did C31 and C32.

[0061] Phenothiazine der...

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Abstract

Tricyclic derivatives of formula (1) for antimicrobial agents, wherein R1 can be alkylsulfonate or sulfonamide. The derivatives are optionally substituted, wherein R2 is hydrogen, halogen, substituted alkyl, thioether or acetyl; Y can be N or C; X can be S, SO, SO2, N, O, CH2, C(O), CO2, NHCO, and Ring B is a 6-, 7-, or 8-membered cycloalkyl ring. The tricyclic derivatives, such as phenothiazine derivatives, can be used to treat pulmonary tuberculosis, especially drug-sensitive and drug-resistant pulmonary tuberculosis. The derivatives of the present invention may be used alone or in combination with known anti-tuberculosis drugs such as ethionamide and ethambutol, and the combination may be administered as a single dose or as two separate doses . The tricyclic derivatives can also be used in the manufacture of drugs for the treatment of tuberculosis.

Description

Technical field [0001] The present invention relates to tricyclic derivatives of phenothiazine, phenoxazine, phenazine, acridine, oxazepine, diazepine, xanthene, and thioxanthene and their uses. Background technique [0002] The phenothiazine antipsychotics and antihistamines prochlorperazine, chlorpromazine and promazine have been demonstrated to have a synergistic interaction with a variety of antimicrobial agents. In the presence of phenothiazine, the minimum inhibitory concentration of these antibiotics is often concentrated to 8,000 times. [0003] It is also known that phenothiazine increases the NADH / NAD ratio of Mycobacterium tuberculosis by inhibiting type II NADH: menaquinone oxidoreductase. As a result, they can increase the reduced state of cells, and can act synergistically with drugs that require fungal thiol (mycothiol) to activate, such as isoniazid and ethionamide. These combination treatments help limit the development of resistance to antimicrobial agents. It ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/5415C07D279/22C07D279/32A61P31/06
CPCA61K45/06A61P31/06C07D279/24A61K31/5415C07D279/22
Inventor 默加马特·安瓦尔·亚尔迪内穆阿扎姆·雅各布斯
Owner UNIVERSITY OF CAPE TOWN
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