Tuberculostatic Action

CNS toxicity occurs because isoniazid has structural similarities to pyridoxine (vitamin Be) and can inhibit its actions. This toxicity is dose-related and more common in slow acetylators. Manifestations include peripheral neuropathy, optic neuritis, ataxia, psychosis and seizures. The administration of pyridoxine to patients receiving INH does not interfere with the tuberculostatic action of INH but it prevents and can even reverse neuritis. Hematological effects include anaemia which is also responsive to pyridoxine. In some 20% of patients antinuclear antibodies can be detected but only in a minority of these patients drug-induced lupus erythematosus becomes manifest. 

Isoniazid, one of the most active of the tuberculostatic drugs, was discovered because it had been shown that nicotinamide exerted some tuberculostatic action (J). A deliberate search for more effective but related chemicals revealed that many pyridine derivatives, including congeners of isonicotinic acid, also were active. Further, it was known that the thiosemicarbazones could inhibit the growth of M. tuberculosis. An attempt to synthesize the thiosemicarbazone of isonicotinaldehyde provided, as the first intermediate compound, isonicotinylhydrazine, or isoniazid. 

Many acylated derivatives of quinoxaline-2,3-dithione have insecticidal and fungicidal properties. Quinoxaline-2,3-dithione cyclic trithiocarbo-nate (Eradex) (25) and 6-methylquinoxaline-2,3-dithione cyclic dithiocar-bonate (Morestan) (26) are particularly effective. 2,3-Bis(carbethoxy-thio)quinoxaline is reported to have tuberculostatic action. ... 

Dopp, W, and H. Bersch. "Tuberculostatic Action of Some Plant Extracts in Vitro." Pharmazie 5 603604,... 

ANTIBIOTIC ACTIVITY Antibacterial action Tuberculostatic action Antifungal action... 

Since aminocoumarins have been found to exert some antibacterial activity [377], investigations were started to explore tuberculostatic activity of various coumarins related to p-aminosalicylic acid (55). 7-Amino-4-methylcoumarin (56) was found to be about one-half, and ffa s-p-aminocinnamic acid (57) one-fourth, as active as p-aminosalicylic acid [392]. The tuberculostatic action of 7-amino-4-methylcoumarin is probably dependent on the opening of the lactone... 

Ethambutol is a synthetic agent and not related to any of the other tuberculostatics. Its mechanism of action is not well understood but in actively dividing mycobacteria it appears to be an inhibitor of mycobacterial RNA synthesis. It also has effects on bacterial phosphate metabolism and on polyamine synthesis. It is an bacteriostatic agent and its main function in combination therapy is to delay the occurrence of resistance, mainly against isoniazid and rifampicin. It is well absorbed after oral administration. It is widely distributed, except to the CNS. Protein binding is about 20-30%. It is mainly excreted unchanged in the bile and urine with an elimination half-life of 3 h. Ethambutol is concentrated in erythrocytes and thus provides a depot for continuous release. 

Several hundred semisynthetic derivatives have been prepared in an effort to obtain substances with better biological activities (for references see Ref.s)). Particularly positions 3 and 4 of the naphthoquinone ring system (numbering system as proposed by Prelog7 8) have been extensively substituted, since it has been shown that structural changes in these two positions do not critically affect the action of the substance on the target enzyme, the bacterial RNA polymerase (cf. Chapter 3.). They can, however, influence other parameters such as its ability to penetrate into cells, its pharmacokinetic properties and resorption, which are all important for clinical use as an antibiotic. Rifampicin (U.S. rifampin), which is a widely used orally active tuberculostatic agent, is a 3-(4-methyl piperazinyl)-iminomethyl derivative of rifamycin SV, synthesized via the 3-formyl derivative (Fig. 5)10 ... 

A group of l,3,4-oxadiazolin-5-ones and l,3,4-oxadiazoline-5-thiones show antitubercular activity.18,43a 76,84 86,181, 132,157 160 They have been investigated with regard to their mode of action. 2-(4 -Pyridyl)-l,3,4-oxadiazolin-5-one (S 57) has shown itself active against Mycobacterium tuberculosis and Mycobacterium leprae.86-158 It possesses some advantages compared with isonicotinic acid hydrazide. Derivatives of S 57 also have some tuberculostatic activity.159, lfl1,162 Further tuberculostatic compounds are derived from p-aminosalicylic acid, for example WS 127 [2-(4 -amino-2 -hydroxyphenyl)-l,3,4-oxadiazoline-5-thione] and WS 174 [2-(4 -acetamido-2 -hydroxyphenyl)-l,3,4-oxadiazolin-5-one].85 2-Cyano-methyl-l,3,4-oxadiazolin-5-one shows a tuberculostatic activity comparable with that of Reazid. 18 Oxadiazolin-5-ones and oxa-... 

The monoamine-oxidase inhibiting type of antidepressants originated from the unexpected central-stimulating effect observed with the tuberculostatic iso-niazid. In the preclinical study of a series of new anti-infectious sulfanilamides, a convulsive effect was observed. An analysis of this unwanted side-effect showed that the convulsions were due to hypoglycemia induced by the anti-infectious sulfanilamide. This hypoglycemic action was recognized as potentially useful... 

Many pyridazine derivatives were tested for analgesic activity,162,487,834-840 for antimicrobial,841-845 tuberculostatic,846,847 and hypoglycemic activity as antidiabetics,848,849 for activity on the central nervous system,850 for anticoccidial,851 insecticidal.852 and fugicidal activity,853 for inhibition of mitochondrial monoamine oxidase,854 for their action on the metabolism of rat cerebral cortex slices,855,856 and against the enzyme... 

The monoamine oxidases are a widespread group of enzymes which catalyse the oxidative deamination of amines to aldehydes (for reviews, see [13, 94, 121, 176, 265]). The prototype of the monoamine oxidase inhibitors, iproniazid, first attracted attention because of its tuberculostatic effect, until it was discovered that it exerted a marked antidepressant action in man. Hypotension was observed as a side effect of iproniazid and numerous other monoamine oxidase inhibitors, and this finally led to the development of one compound belonging to this group-pargyhne-which was specifically intended for use as an antihypertensive. Pargyhne has a gradual onset of action and the hypotension it produces... 

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