Medicinal Chemistry Research Laboratory, MNR College of Pharmacy, Sangareddy - 502 294, Gr. Hyderabad, India.
Faculty of Pharmacy, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai, 600 116, India.
Med Chem. 2021;17(4):352-368. doi: 10.2174/1573406416666200817153033.
Although exhaustive efforts to prevent and treat tuberculosis (TB) have been made, the problem still continues due to multi-drug-resistant (MDR) and extensively drugresistant TB (XDR-TB). It clearly highlights the urgent need to develop novel "druggable" molecules for the co-infection treatment and strains of MDR-TB and XDR-TB.
In this approach, a hybrid molecule was created by merging two or more pharmacophores. The active site of targets may be addressed by each of the pharmacophores and proffers the opportunity for selectivity. In addition, it also reduces undesirable side effects and drug-resistance.
In this study, a novel quinazolinone analog was designed and synthesized by substituting thiourea nucleus and phenyl ring at N-3 and C-2 position of quinazoline ring, respectively. All title compounds were tested for antitubercular activity by in vitro M. tuberculosis and anti-human immunodeficiency virus (HIV) activity by MT-4 cell assay method. The agar dilution method was used to test the antibacterial potency of entire prepared derivatives against various strains of grampositive and gram-negative microorganisms.
The title compounds, 1-(substituted)-2-methyl-3-(4-oxo-2-phenyl quinazolin-3(4H)-yl) isothioureas (QTS1 - QTS15) were synthesized by the reaction between key intermediate 3-amino- 2-phenylquinazolin-4(3H)-one with various alkyl/aryl isothiocyanates followed by methylation with dimethyl sulphate. Among the series, compound 1-(3-chlorophenyl)-2-methyl-3-(4-oxo-2-phenyl quinazolin- 3(4H)-yl) isothioureas (QTS14) showed the highest potency against B. subtilis, K. pneumonia and S. aureus at 1.6 μg/mL. The compound QTS14 exhibited the most potent antitubercular activity at the MIC of 0.78 μg/mL and anti-HIV activity at 0.97 μg/mL against HIV1 and HIV2.
The results obtained from this study confirm that the synthesized and biologically evaluated quinazolines showed promising antimicrobial, antitubercular and anti-HIV activities. The new scaffolds proffer a plausible lead for further development and optimization of novel antitubercular and anti-HIV drugs.
尽管已经付出了彻底防治结核病（TB）的努力，但由于耐多药（MDR）和广泛耐药（XDR）TB 的存在，这一问题仍然持续存在。这清楚地凸显了迫切需要为 MDR-TB 和 XDR-TB 的合并感染治疗和菌株开发新型“可成药”分子。
在这种方法中，通过合并两个或更多药效团来创建混合分子。每个药效团都可以作用于靶标的活性部位，并提供选择性的机会。此外，它还可以减少不良反应和耐药性。
在这项研究中，通过分别在喹唑啉环的 N-3 和 C-2 位置取代硫脲核和苯基环，设计并合成了一种新型的喹唑啉酮类似物。通过体外结核分枝杆菌和抗人免疫缺陷病毒（HIV）活性的 MT-4 细胞测定法，对所有标题化合物进行了抗结核活性测试。采用琼脂稀释法测试了整个制备衍生物对革兰氏阳性和革兰氏阴性微生物各种菌株的抗菌效力。
标题化合物，1-（取代）-2-甲基-3-（4-氧代-2-苯基喹唑啉-3（4H）-基）异硫脲（QTS1-QTS15）通过关键中间体 3-氨基-2-苯基喹唑啉-4（3H）-酮与各种烷基/芳基异硫氰酸酯反应，然后用二甲亚砜甲基化合成。在该系列中，化合物 1-（3-氯苯基）-2-甲基-3-（4-氧代-2-苯基喹唑啉-3（4H）-基）异硫脲（QTS14）对枯草芽孢杆菌、肺炎克雷伯菌和金黄色葡萄球菌的活性最强，MIC 值为 1.6 μg/mL。化合物 QTS14 在 MIC 为 0.78 μg/mL 时表现出最强的抗结核活性，在 0.97 μg/mL 时对 HIV1 和 HIV2 具有最强的抗 HIV 活性。
本研究结果证实，所合成和生物评价的喹唑啉类化合物表现出有希望的抗菌、抗结核和抗 HIV 活性。新支架为进一步开发和优化新型抗结核和抗 HIV 药物提供了合理的先导。
