Kapoor Ekta, Tripathi Vinay, Kumar Vivek, Juyal Vijay, Bhagat Sunita, Ram Veerma
Atma Ram Sanatan Dharma College, New Delhi, India.
Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh, India.
Toxicol Int. 2014 Jan;21(1):69-77. doi: 10.4103/0971-6580.128800.
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 H37RV 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 H37Rv 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.
结核分枝杆菌多重耐药（MDR）发生率的不断上升，正成为包括印度在内的第三世界国家面临的严重公共卫生威胁和社会经济负担之一。在过去几十年里，人们为开发针对耐多药结核分枝杆菌的靶向特异性且具有成本效益的抗菌药物付出了不懈且持续的努力。然而，目前使用的药物仍无法控制耐多药情况的激增。因此，为了解决这一问题，我们合成了一系列对称的反式环己烷-1,4-二胺衍生物，并在结核分枝杆菌H37RV菌株中评估了它们的抗分枝杆菌活性。在合成化合物的不同衍生物中记录到了一系列的疗效，并且发现对位具有异丙基取代的化合物“9u”对受试结核分枝杆菌菌株具有更显著的有害作用。本研究旨在探讨“9u”的有效抗分枝杆菌浓度对人类细胞是否具有生物安全性？将人肺上皮细胞系-A549暴露于一系列浓度下，即“9u”的抗分枝杆菌有效剂量及以上浓度，持续0至96小时。使用细胞毒性的标准终点指标，即溴化四氮唑盐（3-[4,5-二甲基噻唑-2-基]-2,5-二苯基溴化四氮唑）、中性红摄取、乳酸脱氢酶释放、台盼蓝染料排除试验；以及遗传毒性指标，即微核和染色体畸变试验，来评估受试化合物的生物安全性。在暴露于10^(-5) M浓度72小时的A549细胞中，化合物“9u”未显示出显著的细胞毒性和遗传毒性，该浓度远高于杀死结核分枝杆菌H37Rv菌株的浓度。如果给药24小时，发现化合物9u在高达10^(-4) M的浓度下是安全的。数据揭示了化合物9u对结核分枝杆菌具有治疗潜力，且无任何细胞毒性和遗传毒性反应。
