Synthetic Tuberculostats. Iii. Isonicotinaldehyde Thiosemicarbazone and Some Related Compounds

Fox, H. Herbert

doi:10.1021/jo01138a007

Cited by 45 publications

(16 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Perchlozone (1) was synthesized 40 at the Siberian Division of the Russian Academy of Sciences (Novosibirsk, Russia) and is the perchlorate salt of thioureidoiminomethylpyridine, which was first reported in the early 1950s. 41,42 Perchlozone (1) is an analog of thiacetazone (13), a tuberculosis (TB) drug developed in the 1950s that fell out of favor due to adverse side effects. 43 A recent study has proposed that 1 and thiacetazone (13) share a common mode of action: activation by the monooxygenase EthA and inhibition of the FASII dehydratase complex HadABC leading to disruption of mycolic acid biosynthesis.…”

Section: Antibacterial Drugs Launched Since 2000mentioning

confidence: 99%

Antibiotics in the clinical pipeline at the end of 2015

2016

View full text Add to dashboard Cite

There is growing global recognition that the continued emergence of multidrug-resistant bacteria poses a serious threat to human health. Action plans released by the World Health Organization and governments of the UK and USA in particular recognize that discovering new antibiotics, particularly those with new modes of action, is one essential element required to avert future catastrophic pandemics. This review lists the 30 antibiotics and two β-lactamase/β-lactam combinations first launched since 2000, and analyzes in depth seven new antibiotics and two new β-lactam/β-lactamase inhibitor combinations launched since 2013. The development status, mode of action, spectra of activity and genesis (natural product, natural product-derived, synthetic or protein/mammalian peptide) of the 37 compounds and six β-lactamase/β-lactam combinations being evaluated in clinical trials between 2013 and 2015 are discussed. Compounds discontinued from clinical development since 2013 and new antibacterial pharmacophores are also reviewed.

show abstract

Section: Antibacterial Drugs Launched Since 2000mentioning

confidence: 99%

Antibiotics in the clinical pipeline at the end of 2015

2016

View full text Add to dashboard Cite

show abstract

“…Since its discovery as a tuberculostatic agent (12), much work has been done to elucidate its mechanism of action (32). The precise nature of the primary action of isoniazid on the tubercle bacilli is unknown today.…”

mentioning

confidence: 99%

Effect of Isoniazid on the In Vivo Mycolic Acid Synthesis, Cell Growth, and Viability of Mycobacterium tuberculosis

Takayama

Lynn

David

1972

Antimicrob Agents Chemother

276

173

View full text Add to dashboard Cite

When an actively growing culture of the H37Ra strain of Mycobacterium tuberculosis was exposed to isoniazid at a concentration of 0.5 ,g/ml, the cells began to lose their ability to synthesize mycolic acids immediately. After 60 min, the cells had completely lost this ability. The synthesis of the three mycolate components-amycolate, methoxymycolate, and f-mycolate-was inhibited. The viability of the isoniazid-treated cells was unaffected up to about 60 min of exposure, after which time there was a gradual decline in the viability to about 18% after 180 min. Correspondingly, growth of the drug-treated cells slowed down and stopped after 24 hr. The inhibition of the synthesis of mycolic acids was reversible if the drug was removed before the loss of viability set in. Incubation of the viable cells in the absence of the drug for 24 hr restored the mycolate synthesis. These results strongly suggest that the inhibition of the synthesis of the mycolic acids is closely associated with the primary mechanism of action of isoniazid on the tubercle bacilli. The sequence of events which leads to the loss of viability of cells exposed to isoniazid is described.Isoniazid is the mainstay of antituberculosis therapy. Since its discovery as a tuberculostatic agent (12), much work has been done to elucidate its mechanism of action (32). The precise nature of the primary action of isoniazid on the tubercle bacilli is unknown today.One of the more significant early observations was that tubercle bacilli lose their acid-fastness when exposed to isoniazid (14), suggesting that the composition of a certain lipid might be somewhat altered. The altered component could be the mycolic acids which have been implicated in the acidfastness of this organism (11). Studies of several workers suggested an intimate relationship between the effect of the drug and the synthesis of specific lipid components unique to the cell envelope of the tubercle bacilli (4, 10, 25, 26). Recently, Winder and associates found evidence that isoniazid interfered with the formation of the cell envelope, specifically the synthesis of mycolic acids (30,31).We have investigated the effect of isoniazid on the in vivo synthesis of mycolic acids in M. tuberculosis H37Ra using '4C-acetate as the metabolite. We found that isonizaid at a concentration of 0.5 pg/ml immediately began to reduce the cells' ability to synthesize mycolic acids. The gradual decline in viability of the cells began only after complete inhibition of the synthesis of mycolic acids had occurred. In addition, the effect of the drug on the synthesis of mycolates was reversible if the drug was removed before the cells lost their viability. These findings are used to describe the possible mechanism of the action of isoniazid. MATERLALS AND METHODS

show abstract

“…large number of transition metal complexes have been synthesized and charatarised with schiff's bases which have been proved of wide utility, semicarbazone and thiosemicarbazone have joined special attentation due to their activity against protozoa, influenza, small pox, malaria, tuber-culosis [1][2] , and antitumor activity of their meatal complexes. [3][4] Metal complexes of thiosemicarbazone have emerged as new class of chemotherapeutic agent which exhibit inhibitory activity against most cancers through inhibition of a crucial enzyme, obligatory for DNA biosynthesis and cell division.…”

Section: Introductionmentioning

confidence: 99%