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Kapoor E.,Atma Ram Sanatan Dharma College | Tripathi V.,Indian Institute of Toxicology Research | Kumar V.,Indian Institute of Toxicology Research | Juyal V.,Kumaun University | And 2 more authors.
Toxicology International | Year: 2014

Earlier, we had reported the synthesis of a library of symmetrical trans-cyclohexane-1,4-diamine derivatives and evaluated them for their anti-mycobacterium activity in the H37RV strain of Mycobacterium tuberculosis. A range of efficacy was recorded in different derivatives and the compound "9u" having an i-propyl group substitution at the p-position was found to be the most effective. The compound "9u" was found to be safe for cytotoxic and genotoxic responses in human lung epithelium cells-A549, even up to many fold higher than that required to kill M. tuberculosis. Hence, compound "9u" was inferred to be a potential anti-tuberculosis drug of choice. However, the biological safety of compound "9u" upon chronic exposure was still to be answered because anti-tuberculosis (TB) treatment requires a minimum of 6 months exposure of host systems and most of the available anti-TB drugs are known to induce apoptosis, oxidative stress and injury during such exposures. Thus, the present investigations were aimed to study the alterations, if any, in the expression profile (mRNA and protein) of markers associated with apoptosis, injury and oxidative stress in human lung epithelium cells-A549 receiving a chronic exposure of the potential anti-TB compound "9u." Our findings demonstrate that there was a statistically insignificant transient shift (until 3 weeks) in the markers of apoptosis, injury and oxidative stress, after which expression changes were similar to baseline, when compared with unexposed cells of respective time periods. The studied markers showed linearity in the trend at both mRNA and protein level, indicating the suitability of the test system selected in the study. The data confirm the therapeutic potential of compound "9u" for even long-term treatment against M. tuberculosis without having any significant apoptosis, injury and oxidative stress. Source


Kapoor E.,Atma Ram Sanatan Dharma College | Tripathi V.,Indian Institute of Toxicology Research | Kumar V.,Indian Institute of Toxicology Research | Juyal V.,Kumaun University | And 2 more authors.
Toxicology International | Year: 2014

Increasing incidences of multiple drug-resistance (MDR) in Mycobacterium tuberculosis are emerging as one among the serious public health threats and socio-economic burden to the third world countries including India. Last couples of decades are witnesses of the dedicated and sustained efforts made toward the development of target specific and cost-effective antimicrobial agents against MDR-M. tuberculosis. However, the drugs in use are still incapable of controlling the upsurge of MDR. Thus, in order to address the issue, we synthesized a library of symmetrical trans-cyclohexane-1, 4-diamine derivatives and evaluated their anti-mycobacterium activity in H 37 RV strain of M. tuberculosis. A range of efficacy has been recorded in different derivatives of synthesized compounds and compound "9u" having i-propyl group substitution at p-position, was found to have more significant detrimental effects against the tested strain of M. tuberculosis. The present investigations were aimed to study whether the effective anti-mycobacterium concentrations of "9u" are biologically safe to human cells or not? The human lung epithelial cell line-A549 were exposed to a range of concentrations, i.e., at and above the anti-mycobacterium effective dose of "9u" for a period of 0-96 h. The standard endpoints of cytotoxicity viz., tetrazolium bromide salt (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide), neutral red uptake, lactate dehydrogenase release, trypan blue dye exclusion assays; and genotoxicity viz., micronucleus and chromosomal aberrations assays were used to evaluate the bio-safety of test compound. The compound "9u" shows no significant cytotoxicity and genotoxicity in A549 cells exposed to 10 -5 M for 72 h, a concentration substantially higher than the concentration kill the H 37 Rv strain of M. tuberculosis. The compound 9u was found to be safe up to 10 -4 M if given for 24 h. The data reveal the therapeutic potential of compound 9u against M. tuberculosis without any having any cytotoxicity and genotoxicity responses. Source


Kumar N.,University of Delhi | Kapoor E.,Atma Ram Sanatan Dharma College | Singh R.,Translational Health Science and Technology Institute | Kidwai S.,Translational Health Science and Technology Institute | And 3 more authors.
Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry | Year: 2013

A library of symmetrical trans-cyclohexane-1,4-diamine derivatives have been synthesized and evaluated for their activity against the M. tb H 37Rv strain. Most of the synthesized compounds show moderate to weak activity against M. tb H37Rv strain. Out of twenty-seven compounds tested, four compounds having substitution at p-position on the aromatic ring exhibit activity with MIC99 value ranging from 12.5 -25 μM. Compound 9u having i-propyl group substitution at p-position is found to be the most potent among all the tested compounds with MIC99 value of 12.5 μM against M. tb H37Rv strain. All these compounds have also been tested against Methicilin resistant Staphylococcus aureus (MRSA), and four of the compounds 9c, 9i, 9p and 9s possess good antibacterial activity with IC 50 ranging from 128 mg/L -256 mg/L. Source

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