Synthesis and initial testing of novel antimalarial and antitubercular isonicotinohydrazides
Synthesis and initial testing of novel antimalarial and antitubercular isonicotinohydrazides
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DOI：
10.1016/j.rechem.2022.100287
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发表时间：
2022-01-26
影响因子：
2.3
通讯作者：
Yeboah-Manu, Dorothy
中科院分区：
文献类型：
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作者：
Amewu, Richard K.;Ade, Crystal F.;Yeboah-Manu, Dorothy
疟疾和结核病虽然可以治愈和预防，但仍然是全球严重的公共卫生问题，具有破坏性后果。这两种致命疾病的合并感染使情况变得更加复杂，特别是使治疗变得非常困难。由于抗药性的发展，目前治疗疟疾的主要药物正在逐渐失去效力。结核分枝杆菌（Macobacterium tuberculosis，MTB）由于长期治疗而导致患者不依从，对现有抗结核药物产生了多重耐药（Multi-drug Resistance，MDR）和广泛耐药（Extensive Drug Resistance，XDR）。通过引入1，2，4，5-四氧杂环己烷和肼部分合成了一个小的异烟酰肼库。化合物的评价给出抗恶性疟原虫3D 7株的抗疟活性范围为0.060 +/-0.033-0.491 +/-0.012 μ M。我们评估了所选化合物对标准结核分枝杆菌参考菌株H37 Rv和M.使用微孔板Alcohol blue（MABA）测定法对金黄色巨杆菌（一种非结核分枝杆菌）进行了鉴定，发现四种化合物对H37 Rv非常有效，但对金黄色巨杆菌基本上无活性。我们随后估计这些活性化合物的最小抑制浓度，并测试它们对临床M。耐异烟肼（INH）和利福平（RIF）的结核菌株。活性化合物对H37 Rv的MIC在0.003和0.5mg/mL之间，然而，它们对药物抗性临床菌株基本上无活性，除了INH单一抗性抗性菌株，其非常有活性，其中化合物5和8具有0.125mg/mL的MIC。
Malaria and tuberculosis (TB) though curable and preventable, remain serious public health problems globally, with devastating consequences. Co-infection of these two deadly diseases worsens the situation and particularly makes treatment very difficult. The current mainstay for malaria treatment is gradually losing their potency due to the development of resistance. Macobacterium tuberculosis (MTB) has developed Multi-drug Resistance (MDR) and Extensive Drug Resistance (XDR) to current antitubercular drugs due to patient incompliance resulting from long treatment regimen. A small library of isonicotinohydrazide were synthesised by incorporating 1,2,4,5-tetraoxane and hydrazine moieties. Evaluation of the compounds gave antimalarial activities in the range 0.060 +/- 0.033-0.491 +/- 0.012 mu M against 3D7 strain of Plasmodium falciparum. We assessed antimycobacterial activity of selected compounds against the standard Mycobacterium tuberculosis reference strain H37Rv and M. aurum (a non-tuberculous mycobacteria) using the microplate Alamar blue (MABA) assay and found four compounds to be very potent against H37Rv but largely inactive against Macobacterium aurum. We followed up to estimate the minimum inhibitory concentrations of these active compounds and tested them against clinical M. tuberculosis strains resistant to isoniazid (INH) and rifampicin (RIF). The MICs of the active compounds against H37Rv were between 0.003 and 0.5 mg/mL however, they were largely inactive against drug resistant clinical strains except for the INH mono-resistant resistant strain which was very active with compounds 5 and 8 possessing MICs of 0.125 mg/mL.