ABSTRACT
Bacterial DNA topoisomerases are unique in maintaining the DNA topology for cell viability. Mycobacterium tuberculosis [MTB] DNA gyrase, a sole type II topoisomerase has a larger scope as a target for developing novel therapeutics. In this study, an effort was made towards the design and synthesis of benzothiazinone-piperazine hybrid analogues to obtain the possibility of it to lead development through the molecular hybridization technique. A five-step scheme was followed to obtain a series of 36 benzothiazinone-piperazine derivatives and to evaluate them for MTB DNA gyrase inhibition, antimycobacterial and cytotoxicity studies. Compound N-[4-chlorophenyl]-4-[6-nitro-4-oxo-4H-benzo[e][1,3]thiazin-2-yl]piperazine-1-carbothioamide [18] showed greater inhibitory potential with an IC50 of 0.51 +/- 0.16 microM in the DNA supercoiling assay of MTB with a moderate anti-tubercular activity of 4.41 microM. The compound even passed the safety profile of eukaryotic cell cytotoxicity with a 1.81% inhibition in the RAW 264.7 cell line at 100 microM concentration. This study describes the discovery of benzothiazinone as gyrase inhibitors with potent MTB MIC and inhibitory profiles of the gyrase enzyme with less cytotoxic effect. Furthermore, it is believed that this class of compounds has the potential to be further developed as an anti-TB drug candidate
ABSTRACT
Mycobacterium marinum has emerged as a suitable species for induction of tuberculosis-like disease in zebrafish, and various zebrafish models [larval and adult] for drug screening have been proposed in the literature. It is believed that an adult zebrafish model is more useful in drug screening because, apart from assessment of efficacy, one can obtain data on dosage, pharmacokinetics and overall health improvement. This study suggests a simple, cost-effective and resource-efficient protocol for screening of anti-tuberculosis drugs. The parameters used for assessment of infection as well as anti-bacterial response were: [a] bacterial count; and [b] body weight change. An optimization study was conducted to establish the concentration of bacteria required to produce a reproducible phenotype of tuberculosis [TB]. A negative control [Amoxicillin] and anti-mycobacterial drugs [Isoniazid, Rifam-picin, Moxifloxacin, Ethambutol and Isoniazid + Rifampicin] were used for validation of the protocol. All the drugs were administered orally. An intra-peritoneal inoculation of 0.75 million bacteria/fish was optimized for the model. All the anti-tuberculosis drugs showed efficacy in this model, whereas the negative control did not show any signs of reversing the parameters of M. marinum infection. Discussion: Adult zebrafish model of M. marinum-induced tuberculosis has not been fully exploited as a drug screening tool. In the present report, a protocol is suggested that is simple, reproducible and resource-efficient for screening of anti-tuberculosis agents. This protocol is an attempt to refine the published protocols and use this model as a surrogate model of human TB for the purpose of drug screening
ABSTRACT
<p><b>OBJECTIVE</b>To study the effect of halo substitution on disubstituted aryl semicarbazones on the anticonvulsant potential and model the activity based on quantum mechanics.</p><p><b>METHODS</b>A series of twenty-six compounds of N(4)-(4-bromo-3-methylphenyl) semicarbazones were synthesized and evaluated for the anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Some potential compounds were also tested in the subcutaneous strychnine (scSTY) and subcutaneous picrotoxin (scPIC) seizure threshold tests. The synthesized compounds were tested for behavioral impairment and CNS (central nervous system) depression in mice. Quantum mechanical modelling was carried out on these compounds to gain understanding on the structural features essential for activity.</p><p><b>RESULTS</b>Some compounds possessed broad spectrum anticonvulsant activity as indicated by their effect in pentylenetetrazole, strychnine, picrotoxin and maximal electroshock seizures models in resemblance to other aryl semicarbazone derivatives reported earlier. The higher the difference in HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energy levels was, the greater was the activity profile.</p><p><b>CONCLUSION</b>The pharmacophoric requirements for compounds to exhibit anticonvulsant activity that includes one aryl unit in proximity to a hydrogen donor-acceptor domain and an electron donor have been justified with the molecular orbital surface analysis of the synthesized compounds.</p>