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Nowe leki przeciwtrądowe

Nowak K., Suryło P.

Wiadomości Chemiczne

2008

[Z] 62, 5-6

513-531

Leprosy is a chronic infectious disease caused by the bacterium Mycobacterium leprae which has been plaguing mankind for ages. The first effective medicine to treat that illness was dapsone (1946) and it has been used until now [1]. Since then, there has been developed only one more new drug, clofazimine (1), which is, together with dapsone, listed as medicine used to cure leprosy (J 04 BA). The other drugs which are currently employed in leprosy therapy used to be utilised in treatment of other bacterial diseases. Clofazimine (1) was first synthesised in 1954 and has marked antibacterial and anti-inflammatory effects [2-8]. The method of preparation of clofazimine (1) consists of two stages (Scheme 1) [9, 10]. Minocycline (3) is a semisynthetic antibiotic of the tetracycline group with the mycobactericidal activity, obtained by chemical modification of tetracycline derivatives [11-13]. The substrates to synthesise minocycline are the metabolism products of S. aureofaciens or S. psammoticus - 6-demethyltetracycline (4a) or 7-chloro-6-demethyltetracycline (4b) [14-16]. 6-Demethyl-6-deoxyteracycline (5) is obtained as a result of reduction of compounds 4a and 4b, which may be transformed in several ways into minocycline (3) (Scheme 2, 3, 4) [17-30]. Amongst the macrolide antibiotics also the semisynthetic derivatives of erythromycin A, such as clarithromycin (15), azitromycin (16) and telithromycin (17) show some anti-leprosy features [12, 26, 32, 33]. Telithromycin (17) was introduced to medicine in 1995 and belongs to the group of ketolides, the latest generation of macrolides [12, 39, 40-45]. Following the in vitro and in vivo research it has been stated that the fluoroquinolones demonstrate mycobactericidal activity (Table 1) [47-51]. The World Health Organisation (WHO) recommends the use of fluoroquinolones in the multidrug therapy (MDT) together with other chemotherapeutics [108-113]. Rifampicin (26), a drug from the ansamycin antibiotic group, turned out to be an extremely effective weapon against leprosy [72, 73]. It is produced by chemical modification of a fermentation product of S. mediterranei [31, 74]. Rifampicin derivatives rifapentine (27) and rifabutin (28) are manifesting strong reactivity against Mycobacterium leprae, sometimes even surpassing rifampicin (26) (Table 2) [31, 72]. In the treatment of leprosy it is important to cure not only the causes but also the effects of the disease. That is why a wide range of complementary drugs is introduced. Especially steroids such as prednisolone (30), prednisone (31), dexamethasone (32) and fusidic acid (34) are important. The enumerated above steroids have strong anti-inflammatory effects as well as prevent nerve damage leading to smaller and lesser disability [2, 85]. Dexamethasone (32) is particularly efficient in conjunction with azathioprine (33) [90]. In the case of fusidic acid (34) it has been proved that it reveals weak bacteriostatic activity against the Gram-positive bacteria, including Mycobacterium leprae [7, 26]. Leprosy treatment involves the use of huge doses of bactericidal and bacteriostatic drugs what may lead to a life-threatening shock. In such circumstances, the most valuable medicine seems to be thalidomide (35) [82, 102-105]. WHO has prepared some programmes of leprosy treatment, recommending a diversion from a single drug to multidrug therapy (MDT). Implementation of the MDT therapy brings about numerous advantages such as economic advantages, shortening of treatment time and particular drug resistance prevention [7, 11, 107-109]. Leprosy, despite the tiny number of effective medicines, is totally curable. There have been continuous signals about utilising common and popular antibacterial drugs in leprosy treatment. Yet, it should be taken into consideration, that all action taken against that disease is limited to fighting bacteria but not preventing transmission.

Leki przeciwtrądowe

Nowak K., Suryło P.

Wiadomości Chemiczne

2006

[Z] 60, 3-4

257-278

Leprosy is a chronic infectious disease, that is caused by a bacillus of Mycobacterium leprae. It was considered to be an incurable disease for ages. Nowadays leprosy is a vanishing disease although you can meet it principally in the tropical zone countries. Since times immemorial, the natural origin preparations had been involved under the leprosy treatment. One of them was chaulmoogra, the oil isolated from seeds of: Hydnocarpus kurzii, the gorli tree - Oncoba echinata and Carpotroche brasiliensis plant. The main components of the chaulmoogra oil are triglicerides of hydnocarpic acid, chaulmoogric acid as well as gorlic. In 1921 year, ethyl esters of named above acids were applied successfuUy in the leprosy treatment. Other natural origin components also reveal leprostatic effectiveness. There are derivatives of boswelin acid which have been found in the Boswelia serrata plant. The first and effectively applied antileprosy drug up today, occured Dapsone, which was intro-duced in the leprosy therapy in 1946 year. This medicine has appeared comparatively little toxic, inexpensive and effective at all forms of leprosy. A great number of Dapsone derivatives have been received lately. Most of them have been introduced to the therapy of leprosy and other bacterial diseases. The next group of derivatives of Dapsone composes the ones, with substitutions in the phenyl ring 15. Such combinations are received in result of a multistage synthesis. There have been still lasting experiments above receiving new active sulfones in relation to bacillus of Mycobacterium leprae. Among sulfones not being derivatives of Dapsone Promizole has been found and applied in the leprosy therapy. Except sulfones, sulfonamides are also employed in the leprosy therapy, in spite that theirs activity in relation to Mycobacterium leprae is smali. After all, Sulfomethoxazole gives good therapeutic results in connection with Trimethoprim. These connections are being utilised in a multidrug, antileprosy therapy. There are a few methods of receiving of Sulfomethoxazole and Trimethoprim. The derivatives of Trimethoprim, Brodimoprim and Epiroprimhave been received by the Swiss. Hoffmann-La-Roche Ltd Company and they are likely to be used in the multidrug antileprosy therapy. It has been taken an advantage in the leprosy treatment of using derivatives of thiocarbamide -Tiambutazyne and Thiocarlide. However the need to engage them in large doses is the basie defect of these medicines. Tiambutozyne has being received as a result of the p-amine-N,N--dimethylaniline reaction witch p-propoxyphenylisothiocyanate, however Thiocarlide synthesis depends on the 4-(3-methylbutoxy)aniline reaction with carbon disuflide. There are also some amides e.g. Ethionamide, Prothionamide as well as Pyrazinamide which produce a good antileprosy influence. These medicines have found the application mainly in the tuberculosis treatment, though in the antileprosy therapy either. Still, the experiments on new effective working antileprosy combinations have been carrying out. According to results, good antileprous proprieties have characterized the derivatives of thiazolidine and thiocarbamide. Searching for new antileprosy medicines have still been led in the sulfons and sulfonamides groups. A number of new medicines has entered the therapy of leprosy at present and among others there are chiefly ansamycin, chinolones and ketholides antibioties. However Dapsone has still been fulfilling the most important part 6, which for over of 60 years continually has been determining the basie antileprosy medicine.