Tuberculostatic property

The humulones 23a-d have been known for many years, but they can still be considered as a topical family of natural products (Figure 8). Found in hop resins and brewing hops, these natural ortho-quinols aroused early interest because of their antibiotic and tuberculostatic properties. Oxidative dearomatizing hydroxylation of their phenolic parents 24a-d was used in their synthesis [1]. 

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 ... 

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. ... 

As synthesis intermediates are chemically connected to final products, and as they often present some common groupings with them, it is not inconceivable that they share some pharmacological properties. For this reason, it is always prudent also to submit these compounds to a pharmacological evaluation. Among drugs discovered in this way are the tuberculostatic semicarbazones they were initially used in the synthesis of antibacterial sulfathiazoles. Subsequent testing of isonicotinic acid hydrazide, destined for the synthesis of a particular thiosemicarbazone, revealed the powerful tuberculostatic activity of the precursor which has since become a major antitubercular drug (isoniazide). 

Isoniazid (isonicotinoylhydrazine, inH) (26 R = 4-C5H5N) is a commonly used tuberculostatic drug with an activity increased by the presence of Cu ions. The structure of the mono chelate formed with Cu Cl2 shows the compound to coordinate through the O and N atoms. This same coordination mode is present in an Mn chelate. A report of the preparation and properties of several 1 1 and 2 1 complexes formed with inH and Mn , Fe , Co , Ni , Cu and Zn" has appeared recently. Bridged polymeric structures were concluded for compounds of general form [M(inH)2X2] (X = Cl or Br), but N deprotonation resulted in the more common N—O bidentate behaviour in the compounds [Cu"(in)Cl]H20 and tCu (in)Br]. 

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