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In this study, we report the synthesis of a series of chalcone–benzoxaborole hybrid molecules and the evaluation of their anticancer activity. Their anticancer potency and toxicity were tested on three human cancer cell lines and two normal cell lines. The 4-fluoro compound 15 was found to be the most potent compound with an IC 50 value of 1.4 μM on SKOV3 cells. The 4-iodo compound 18 and 3-methyloxy-4-amino compound 47 showed good potency on SKOV3 cells while exhibiting low toxicity on normal cells. This work extended the application of benzoxaboroles to the field of anticancer research. [ABSTRACT FROM AUTHOR]

Abstract: Human African trypanosomiasis is a fatal parasitic infection caused by the protozoan Trypanosoma brucei. The development of novel antitrypanosomal agents is urgently needed. Here we report the synthesis and structure–activity relationship of a new class of benzoxaboroles as antitrypanosomal agents. These compounds showed antiparasitic IC50 values ranging from 4.02 to 0.03 μg/mL and satisfactory cytotoxicity profile. Three of the lead compounds were demonstrated to cure the parasitic infection in a murine acute infection model. The structure–activity relationship of the pyrrolobenzoxaboroles are also discussed. [Copyright &y& Elsevier]

Abstract: A series of new boron-containing benzoxaborole compounds was designed and synthesized for a continuing structure–activity relationship (SAR) investigation to assess the antimalarial activity changes derived from side-chain structural variation, substituent modification on the benzene ring and removal of boron from five-membered oxaborole ring. This SAR study demonstrated that boron is required for the antimalarial activity, and discovered that three fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles (9, 14 and 20) have excellent potencies (IC50 0.026–0.209μM) against Plasmodium falciparum. [Copyright &y& Elsevier]

Abstract: As the best-characterized ubiquitin-like protein (UBL), small ubiquitin-related modifier (SUMO) was found to conjugate with a number of proteins to regulate cellular functions including transcription, signal transduction, and cell cycle. While E1, E2 and E3 ligases are responsible for the forward SUMOylation reaction, SUMO-specific proteases (SENPs) reversibly remove SUMO from the SUMOylated proteins. Recently, SENP1 was found to be a potential therapeutic target for the treatment of prostate cancers, but the design and synthesis of its inhibitors have not been reported. We designed and synthesized a series of benzodiazepine-based SENP1 inhibitors, and they showed inhibitory activity as good as IC50 =9.2μM (compound 38). The structure–activity relationship was also discussed. [Copyright &y& Elsevier]

• Starting from initial hit compound 1 , a series of benzhydrol-oxaborole hybrid compounds were designed and synthesized as inhibitors of S. pneumoniae LeuRS. • Structure-based optimization led to the discovery of compound 46 and 54 , which showed improved potency (IC 50 = 0.368 and 0.950 μM) when compared with parent compound 1. • The co-crystal of compound 54 in the editing domain pocket of Sp LeuRS was obtained and revealed the binding mode of compound 54. Pneumonia caused by bacterium S. pneumoniae is a severe acute respiratory infectious disease with high morbidity and mortality, especially for children and immunity-compromised patients. The emergence of multidrug-resistant S. pneumoniae also presents a challenge to human health. Leucyl-tRNA synthetase (LeuRS) catalyzes the attachment of l -leucine to tRNALeu, which plays an essential role in protein translation and is considered an attractive antimicrobial drug target. In the present work, benzhydrol-oxaborole hybrid compounds were designed and synthesized as inhibitors of S. pneumoniae LeuRS. Exploration of the phenyl ring near Lysine 389 eventually yielded compounds 46 and 54 with submicromolar inhibitory potency. The co-crystal of compound 54 in the editing domain pocket of Sp LeuRS was obtained and confirmed the formation of an additional hydrogen bond between the carbonyl of 54 and Lysine 389. It also showed anti-pneumococcal activity in vitro. The structure–activity relationship was discussed. This work will provide an essential foundation for the further development of anti-pneumococcal agents by targeting LeuRS. [ABSTRACT FROM AUTHOR]

The SUMO (small ubiquitin-related modifier)-specific proteases (SENPs) are responsible for the cleavage of SUMO from its target proteins, thus play important roles in the dynamic SUMOylation and deSUMOylation processes. SENPs are related to a variety of human diseases including cancer and represent a new class of potential therapeutic targets with mechanism of action that is likely to be different from that of current clinically used drugs. However, potent inhibitors that are selective within the SENPs family members still remain a challenge due to their high homology. In order to demonstrate the feasibility of developing selective inhibitors within the SENPs family, we chose SENP1/2/5 as representatives, aiming to identify inhibitors with selectivity among the members. Starting from a hit compound ZCL951 from virtual screening, a series of benzothiophene-2-carboxamide inhibitors were designed based on the protein structures of SENP1, 2, and 5. First, an unoccupied hydrophobic pocket was first identified which led to IC 50 as low as 0.56 μM. Furthermore, the ethylacetate 77 gave both submicromolar inhibitory activity and 33-fold selectivity for SENP2 versus SENP5. They are the most potent and selective nonpeptidic inhibitor reported so far for the SENPs family, as far as we are aware. Their structure-activity relationship was also discussed. Image 1 • Starting from ZCL951 , a series of benzothiophene-2-carboxamide SENPs inhibitors were designed. • An unoccupied hydrophobic pocket was first identified which led to IC 50 as low as 0.56 μM. • Compound 77 gave a 33-fold selectivity of SENP2 vs. SENP5. • These compounds represent the most potent and selective nonpeptidic inhibitors reported so far for the SENPs family. [ABSTRACT FROM AUTHOR]

Human African trypanosomiasis (HAT), caused by the parasitic protozoa Trypanosoma brucei , is one of the fatal diseases in tropical areas and current medicines are insufficient. Thus, development of new drugs for HAT is urgently needed. Leucyl-tRNA synthetase (LeuRS), a recently clinically validated antimicrobial target, is an attractive target for development of antitrypanosomal drugs. In this work, we report a series of α-phenoxy- N -sulfonylphenyl acetamides as T. brucei LeuRS inhibitors. The most potent compound 28g showed an IC 50 of 0.70 μM which was 250-fold more potent than the starting hit compound 1. The structure-activity relationship was also discussed. These acetamides provided a new scaffold and lead compounds for the further development of clinically useful antitrypanosomal agents. Image 1 • An α-phenoxy- N -sulfonylphenyl acetamide scaffold discovered to inhibit Tb LeuRS with good potency. • A series of new Tb LeuRS inhibitors synthesized and a structure-activity relationship discussed. • Compound 28g showed an IC 50 as low as 0.70 μM. [ABSTRACT FROM AUTHOR]