Abstract[1,2,4]Triazolo[1,5‐a]pyrimidine is an important heterocyclic scaffold known to have a wide range of pharmacological activities such as anticancer, antimicrobial, anti‐tubercular, CB2 cannabinoid agonists, feticide, and adenosine antagonists. Several clinical trials and marketed drugs such as Trapidil, Essramycin, Pyroxsulam, DSM‐265, Flumetsulam, GNF‐6702, and Cevipabulin indicate the potential of [1,2,4]triazolo[1,5‐a]pyrimidine moiety with various functional groups in medicinal chemistry. Herein, we represent a concise report focusing on the synthetic strategies used for diversely substituted [1,2,4]triazolo[1,5‐a]pyrimidine analogs and their pharmacological applications. To the best of our knowledge, since 1980, we are the first to write a review on this emerging scaffold, which reveals the synthetic strategies, and pharmacological activities of differently substituted [1,2,4]triazolo[1,5‐a]pyrimidine with special emphasis on structure‐activity relationship studies.

08 Oct 2020·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases

Q1 · MEDICINE

Article

Author: Rudewicz, Patrick J. ; Wiesmann, Christian ; Supek, Frantisek ; Chen, Yen-Liang ; Berman, Ashley ; Tuntland, Tove ; Yeh, Vince ; Richmond, Wendy ; Davis, Lauren C. ; Kreishman-Deitrick, Mara ; Nagle, Advait ; Shapiro, Michael ; Liu, Xiaodong ; Smith, Jeffrey ; Pybus, Brandon ; Srinivas, Honnappa ; Ballard, Jaime ; Molteni, Valentina ; Johnson, Kevin ; Groessl, Todd ; Thompson, Christopher ; Glynne, Richard J. ; Khare, Shilpi ; Luneau, Alexandre ; Bursulaya, Badry ; Liu, Xianzhong ; Jiricek, Jan ; Be, Celine ; Mathison, Casey J. N. ; Chianelli, Donatella ; Lerario, Isabelle ; Lai, Yin H. ; Gibney, Michael ; Xie, Yongping ; Rao, Srinivasa P. S. ; Biggart, Agnes ; Gao, Mu-Yun ; Caridha, Diana ; Eggimann, Fabian Kurt ; Sciotti, Richard J. ; Spraggon, Glen ; Hein, Andreas ; Liang, Fang

Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis. Here, we describe the discovery and characterization of LXE408, a structurally related kinetoplastid-selective proteasome inhibitor currently in Phase 1 human clinical trials. Furthermore, we present high-resolution cryo-EM structures of the Leishmania tarentolae proteasome in complex with LXE408, which provides a compelling explanation for the noncompetitive mode of binding of this novel class of inhibitors of the kinetoplastid proteasome.

26 Jul 2017·Chemistry – A European JournalQ2 · CHEMISTRY

Sulfur–Fluoride Exchange (SuFEx)‐Mediated Synthesis of Sterically Hindered and Electron‐Deficient Secondary and Tertiary Amides via Acyl Fluoride Intermediates

Q2 · CHEMISTRY

Article

Author: Spiteri, Christian ; Barrow, Andrew S. ; Giel, Marie‐Claire ; Smedley, Christopher J. ; Sharma, Pallavi ; Moses, John E.

AbstractAmide bond formation is one of the most executed reactions in chemistry and biology. This is largely due to the ubiquity of the amide functional group in biological molecules, natural products and pharmaceutically important drugs. We report here the development of “SuFExAmide”: a new sulfur–fluoride exchange (SuFEx) click chemistry based protocol for the efficient amidation of carboxylic acids via acyl fluoride intermediates. We have developed benzene‐1,3‐disulfonyl fluoride as a cost effective, powerful and versatile coupling agent, which delivers challenging secondary and tertiary amides in excellent yields from sterically hindered and electron‐deficient amines. The straightforward method offers significant benefits over existing protocols in terms of substrate scope, efficiency and ease of operation and is demonstrated by the synthesis of 44 amides, including GNF6702, an antiprotozoal drug candidate. In the majority of cases, the amide products are obtained in high yield without the need for excess reagents or chromatographic purification.

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Indication	Highest Phase	Country/Location	Organization	Date
Leishmaniasis	Phase 1	GB	Wellcome Trust Clinical Research Facility	-
Chagas Disease	Preclinical	GB	Wellcome Trust Clinical Research Facility	-
Infection by Trypanosoma brucei brucei	Discovery	GB	Wellcome Trust Clinical Research Facility	-

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