Department of Biochemistry, Faculty of Life Sciences, University of Central Punjab, Lahore 54590, Pakistan.
Department of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom.
Bioorg Chem. 2020 Dec;105:104425. doi: 10.1016/j.bioorg.2020.104425. Epub 2020 Oct 24.
Fused diaza-heterocycles constitute the core structure of numerous bioactive natural products and effective therapeutic drugs. Among them, phthalazines have been recognized as remarkable structural leads in medicinal chemistry due to their wide application in pharmaceutical and agrochemical industries. Accessing such challenging pharmaceutical agents/drug candidates with high chemical complexity through synthetically efficient approaches remains an attractive goal in the contemporary medicinal chemistry and drug discovery arena. In this review, we focus on the recent developments in the synthetic routes towards the generation of phthalazine-based active pharmaceutical ingredients and their biological potential against various targets. The general reaction scope of these innovative and easily accessible strategies was emphasized focusing on the functional group tolerance, substrate and coupling partner compatibility/limitation, the choice of catalyst, and product diversification. These processes were also accompanied by the mechanistic insights where deemed appropriate to demonstrate meaningful information. Moreover, the rapid examination of the structure-activity relationship analyses around the phthalazine core enabled by the pharmacophore replacement/integration revealed the generation of robust, efficient, and more selective compounds with pronounced biological effects. A large variety of in silico methods and ADME profiling tools were also employed to provide a global appraisal of the pharmacokinetics profile of diaza-heterocycles. Thus, the discovery of new structural leads offers the promise of improving treatments for various tropical diseases such as tuberculosis, leishmaniasis, malaria, Chagas disease, among many others including various cancers, atherosclerosis, HIV, inflammatory, and cardiovascular diseases. We hope this review would serve as an informative collection of structurally diverse molecules enabling the generation of mature, high-quality, and innovative routes to support the drug discovery endeavors.
稠环杂环构成了许多生物活性天然产物和有效治疗药物的核心结构。其中，酞嗪因其在制药和农用化学品工业中的广泛应用而被认为是药物化学中显著的结构先导物。通过合成效率高的方法获得具有高化学复杂性的此类具有挑战性的药物制剂/候选药物仍然是当代药物化学和药物发现领域的一个有吸引力的目标。在这篇综述中，我们重点介绍了合成路线的最新进展，这些路线用于生成基于酞嗪的活性药物成分及其针对各种靶标的生物潜力。强调了这些创新且易于获得的策略的一般反应范围，重点是官能团耐受性、底物和偶联伙伴的兼容性/局限性、催化剂的选择和产物多样化。在适当的情况下，这些过程还伴随着对反应机制的深入了解，以展示有意义的信息。此外，通过药理学取代/整合围绕酞嗪核心进行的结构-活性关系分析的快速检查，揭示了生成具有显著生物学效应的稳健、高效和更具选择性的化合物的可能性。还采用了大量的计算方法和 ADME 分析工具，对二氮杂环化合物的药代动力学特征进行全面评估。因此，新结构先导物的发现有望改善各种热带疾病（如结核病、利什曼病、疟疾、恰加斯病等）的治疗效果，同时还包括各种癌症、动脉粥样硬化、HIV、炎症和心血管疾病等。我们希望这篇综述将成为一个信息丰富的结构多样分子集合，为支持药物发现工作提供成熟、高质量和创新的路线。
