Recent Advances in the Synthesis and Biological Activity of Pyrrolo[2,3-c]pyridines

Original Research http://ophcj.nuph.edu.ua UDC [547.759+547.83]:54.057 V. V. Voloshchuk1,2, S. P. Ivonin1 Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, 5 Academician Kukhar str., 02098 Kyiv, Ukraine 2 Enamine Ltd., 78 Winston Churchill str., 02094 Kyiv, Ukraine 1 Recent Advances in the Synthesis and Biological Activity of Pyrrolo[2,3-c]pyridines Abstract Pyrrolo[2,3-c]pyridines (6-azaindoles) are the most promising nitrogen-containing heterocyclic compounds in the field of drug development. Exhibiting extraordinary versatility as pharmacophores, they are widely used in the development of kinase inhibitors, antiproliferative agents, and as potential therapeutic agents for the treatment of various diseases, including cancer and Alzheimer’s disease. A large number of works focusing on new methods and approaches in the synthesis of 6-azaindoes, as well as on the study of their biological activity, have been published worldwide. In our review, we tried to classify all currently known strategies for the construction of the 6-azaindole core, which were published within the last 15 years, the chemical diversity of the derivatives obtained, and their therapeutic potential in the context of medicinal chemistry. We hope that this work will generalize and facilitate the understanding of the strategy for the synthesis of pyrrolo[2,3-c]pyridines, as well as help scientists in their further research in the direction of 6-azaindoles. Keywords: pyrrolo[2,3-c]pyridines; 6-azaindoles; biological activity; medicinal chemistry; heterocyclic compounds; drug development В. В. Волощук1,2, С. П. Івонін1 1 Інститут органічної хімії Національної академії наук України, вул. Академіка Кухаря, 5, м. Київ, 02660, Україна 2 ТОВ НВП «Єнамін», вул. Вінстона Черчилля, 78, м. Київ, 02094, Україна Останні досягнення в синтезі та біологічній активності піроло[2,3-c]піридинів Анотація Піроло[2,3-c]піридини (6-азаіндоли) є одними з найперспективніших серед азотовмісних гетероциклічних сполук у сфері розробки ліків. Виявляючи надзвичайну універсальність як фармакофори, вони відіграють ключову роль у розробці інгібіторів кіназ, антипроліферативних агентів та постають потенційними терапевтичними агентами для лікування різноманітних захворювань, зокрема раку та хвороби Альцгеймера. У світі опубліковано велику кількість робіт, зосереджених на нових методиках та підходах у синтезі 6-азаіндолів, а також на дослідженні їхньої біологічної активності. У нашому огляді ми намагалися класифікувати всі відомі на сьогодні стратегії конструювання 6-азаіндольного ядра, опубліковані за останні 15 років, розглянути хімічне різноманіття одержаних похідних та їх терапевтичний потенціал у контексті медичної хімії. Ми сподіваємось, що ця робота узагальнить та полегшить розуміння стратегій синтезу піроло[2,3-c]піридинів, а також допоможе науковцям у їхніх подальших дослідженнях 6-азаіндолів. Ключові слова: піроло[2,3-c]піридини; 6-азаіндоли; біологічна активність; медична хімія; гетероциклічні сполуки; розробка ліків Citation: Voloshchuk, V. V.; Ivonin, S. P. Recent advances in the synthesis and biological activity of pyrrolo[2,3-c]pyridines. Journal of Organic and Pharmaceutical Chemistry 2024, 22 (1), 33 – 56. https://doi.org/10.24959/ophcj.24.303972 Received: 13 April 2024; Revised: 7 May 2024; Accepted: 10 May 2024 Copyright© 2024, V. V. Voloshchuk, S. P. Ivonin. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0). Funding: The authors received no specific funding for this work. Conflict of interests: The authors have no conflict of interests to declare. ISSN 2308-8303 (Print) / 2518-1548 (Online) 31 Журнал органічної та фармацевтичної хімії 2024, 22 (1) ■ Introduction Nitrogen-containing heterocyclic compounds play one of the central roles in the realm of drug development, mainly thanks to their inherent molecular polarity, water solubility, and the ability to permeate cellular membranes. The analysis of FDA-approved drugs reveals that an astonishing 59 % of unique small-molecule drugs contain at least one nitrogen heterocycle, which demonstrates their importance in drug design and discovery [1]. This predominance is attributed not only to the versatility of nitrogen heterocycles in mimicking the biological landscape, but also to their structural diversity, which offers myriad possibilities for the modulation of pharmacokinetic and pharmacodynamic properties. Among all of the nitrogen-containing heterocycles, pyrrolo[2,3-c]pyridines stand out as a very promising scaffold due to its unique structural features and considerable biological activity. This class of compounds with the condensed pyrrole and pyridine ring has long attracted a widespread interest from the research community. This interest is demonstrated by the vast list of literature on synthetic methodologies, structural modifications, and the study of the medicinal and biological potential of the 6-azaindole core. The review by Popowycz et al. (2007) meticulously summarized this data, highlighting the versatility of 6-azaindoles in drug development and underscoring the synthesis of compounds via diverse strategies, including the Reissert, BatchoLeimgruber, Hemetsberger-Knittel syntheses, and their functionalization in various positions to enhance the biological activity [2]. It delves into the design of 6-azaindoles as biological targets and demonstrates their potential across a range of applications, from therapeutic agents to key synthetic intermediates. However, since 2007, the synthesis and functionalization capabilities of pyrrolo[2,3-c]pyridines have significantly expanded due to advancements in synthetic chemistry, the availability of new reagents, increased technical capabilities, and so on. This synthetic versatility combined with the inherent biological relevance of the pyrrolo[2,3-c]pyridine core has led to the emergence of an immense amount of research, publications, and scientific works over the past 17 years. Therefore, it seems to be very reasonable to complement the work of Popowycz, conduct a thorough analysis of all the new scientific achievements and provide a fresh thorough overview 32 of the current state of research on pyrrolo[2,3-c]pyridines, encompassing their synthesis, structural modifications, and pharmacological potential. By studying the current scientific developments in this field and identifying promising areas for future research, we hope to contribute to the ongoing efforts to use pyrrolo[2,3-c]pyridines in the search for new therapeutic agents. ■ Results and discussion Pyrrolo[2,3-c]pyridines and their annulated derivatives can be synthesized by various synthetic strategies. However, it makes sense to highlight three main principal approaches that stand out due to their efficiency and versatility: (1) the annulation of the pyrrole nucleus to the pyridine cycle; (2) the annulation of the pyridine nucleus to the pyrrole cycle; (3) the sync (...truncated)