Abstract
Tuberculosis (TB) is a severe infectious disease with high mortality and morbidity. The emergence of drug-resistant TB has increased the challenge to eliminate this disease. Isoniazid (INH) remains the key and effective component in the therapeutic regimen recommended by World Health Organization (WHO). A series of isoniazid-carborane derivatives containing 1,2-dicarba-closo-dodecaborane, 1,7-dicarba-closo-dodecaborane, 1,12-dicarba-closo-dodecaborane, or 7,8-dicarba-nido-undecaborate anion were synthesized for the first time. The compounds were tested in vitro against the Mycobacterium tuberculosis (Mtb) H37Rv strain and its mutant (ΔkatG) defective in the synthesis of catalase-peroxidase (KatG). N′-((7,8-dicarba-nido-undecaboranyl)methylidene)isonicotinohydrazide (16) showed the highest activity against the wild-type Mtb strain. All hybrids could inhibit the growth of the ΔkatG mutant in lower concentrations than INH. N′-([(1,12-dicarba-closo-dodecaboran-1yl)ethyl)isonicotinohydrazide (25) exhibited more than 60-fold increase in activity against Mtb ΔkatG as compared to INH. This compound was also found to be noncytotoxic up to a concentration four times higher than the minimum inhibitory concentration 99% (MIC99) value.
Highlights
According to the World Health Organization (WHO), tuberculosis (TB) causes the highest number of deaths due to infectious disease worldwide
The newly synthesized INH analog containing para-carborane cluster 3 (Figure 2), The newly synthesized INH analog containing para-carborane cluster 3 (Figure 2), instead of a instead of a pyridine ring, was obtained in a simple three-step procedure: (1) the pyridine ring, was obtained in a simple three-step procedure: (1) the synthesis of 1,12-dicarba-clososynthesis of 1,12-dicarba-closo-dodecaborane-1-carboxylic acid (1) [20], (2) the synthesis of dodecaborane-1-carboxylic acid (1) [20], (2) the synthesis of 1,12-dicarba-closo-dodecaborane-11,12-dicarba-closo-dodecaborane-1-carboxylic acid chloride (2) [20], and (3) the synthesis of carboxylic acid chloride (2) [20], and (3) the synthesis of 1,12-dicarba-closo-dodecaborane-11,12-dicarba-closo-dodecaborane-1-carboxylic acid hydrazide (3). This synthesis was performed carboxylic acid hydrazide (3). This synthesis was performed in one glass flask, and the yield of in one glass flask, and the yield of product 3 after isolation and purification by column chromatography product 3 after isolation and purification by column chromatography was 41%
In the search for new antitubercular agents, we developed a method for the synthesis of INH
Summary
According to the World Health Organization (WHO), tuberculosis (TB) causes the highest number of deaths due to infectious disease worldwide. Prodrug INH, an isonicotinic acid-derivative hydrazide (pyridine-4-carbohydrazide), is activated in bacilli by catalase-peroxidase (KatG) to form the INH-nicotinamide adenine dinucleotide (NAD). (KatG) to form the INH-nicotinamide adenine dinucleotide (NAD) adduct This adduct inhibits the enzyme enoyl-acyl carrier protein reductase (InhA) of the fatty acid synthase II (FASII), leading to the growth inhibition or death of bacilli. INH is a first-line drug of mutations in katG, as well as in the promoter region of inhA, are the primary mechanisms of rerecommended by WHO in the treatment of drug-sensitive tuberculosis [5]. The accumulation of sistance to INH responsible for about 75% of all causes of Mtb resistance to INH in clinical settings mutations in katG, as well as in the promoter region of inhA, are the primary mechanisms of resistance [6,7]. The INH-resistant strains carrying mutations in the ndh, kasA, or oxyR-ahpC intergenic regions to INH responsible for about 75% of all causes of Mtb resistance to INH in clinical settings [6,7]
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