Novel Isoniazid-Carborane Hybrids Active In Vitro against Mycobacterium tuberculosis

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.

Design of DNA Intercalators Based on 4-Carboranyl-1,8-Naphthalimides: Investigation of Their DNA-Binding Ability and Anticancer Activity

“…The donor-acceptor distance is 3.16 Å, indicating a relatively strong bond for a carbon atom acting as a donor. This is another confirmation that the carborane groups can participate in weak H-bonding interactions [9,19], and the acidic nature of the C-H group was previously observed for free carboranes [33].…”

“…Progressive addition of ct-DNA at the concentration of 1.25-15 µM to a fixed amount of modified naphthalic anhydride or naphthalimide (10 µM concentration) decreased absorbance for almost all the tested modified conjugates, except conjugates 14, 15, and 22-27 for which changes in absorbance were not observed. For all other conjugates, the absorption spectra demonstrated no bathochromic effect (6-10, 16, 18, 36-43, 54, 56, 58, 60, and 61) or slight bathochromic shifts (11,17,19, 55, and 59) (1-2 nm). It should be noted that mitonafide also caused a small bathochromic shift, which was confirmed in our study [9] and the literature [41].…”

“…The properties of boron clusters that are critical to their use in medicinal chemistry include abiotic origin (these are therefore chemically and biologically orthogonal to native cellular components), the unique interaction properties of boron clusters and their derivatives with biomolecules, lipophilicity, amphiphilicity, hydrophobicity (depending on the chemical structure), chemical stability, susceptibility to functionalization, spherical or ellipsoidal geometry, and rigid three-dimensional arrangement [14,15]. As reported earlier, the introduction of boron clusters into drug molecules could improve the activity toward resistant forms [16][17][18][19] or to obtain hitherto unknown nematicidal activity [20]. Structures of mitonafide, pinafide, and 1,8-naphthalimides modified with a carborane cluster [8,9].…”

Physiologically Active Compounds Based on Membranotropic Cage Carriers–Derivatives of Adamantane and Polyhedral Boron Clusters (Review)

“…A number of isoniazid derivatives of carborane 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 [ 72 ]. The compounds were tested in vitro against the Mycobacterium tuberculosis (Mtb) H37Rv strain and its mutant (ΔkatG), deficient in catalase-peroxidase synthesis (KatG).…”

Microwave-Assisted Synthesis of Schiff Bases of Isoniazid and Evaluation of Their Anti-Proliferative and Antibacterial Activities

“…It was observed that in recent years, isoniazid and its derivatives have received attention and are being widely studied. The derivatives of isoniazid are evaluated for their various biological activities, such as anti-inflammatory [8], anticancer [9,10], antimicrobial [11][12][13], anti-tubercular [2,11,[14][15][16][17], and in the treatment of Alzheimer's disease [18].…”