ACS Medicinal Chemistry Letters最新文献

Phosphodiesterases (PDEs) have drawn attention due to their critical roles in physiological and pathological conditions. Many research groups have studied these hydrolytic enzymes to develop new drugs, including apremilast as a PDE4 inhibitor and sildenafil as a PDE5 inhibitor. Targeting PDE7 has also been deemed a rational strategy to ameliorate autoimmune conditions. However, to date, no successful clinical results have been reported. We postulated that progress in these studies with PDE7 had been hampered by the lack of a potent ligand with a reasonable selectivity for this PDE isozyme. Therefore, starting from a PDE7A/7B dual inhibitor, our investigations led to improved selectivity along with extended metabolic stability, resulting in a novel PDE7A inhibitor 26. This compound with high selectivity over the closest isozyme is an ideal chemical entity to unveil new pharmacological roles of PDE7A-dependent signaling, as exemplified by the in vivo antiosteoporotic effects.

The tetrazole group is here proposed as a zinc-binding warhead for the inhibition of the metalloenzyme carbonic anhydrases. A set of synthesized derivatives incorporating the tetrazole moiety were evaluated as inhibitors against a panel of human isoforms, exhibiting K _I values spanning between the submicromolar and low-to-medium micromolar ranges (0.62-19.6 μM). X-ray crystallographic studies were conducted to gain insights into their modes of binding to the target enzyme. These findings mark a significant advancement in the search for inhibitory chemotypes other than classical sulfonamides.

Multidrug-resistant pathogens pose a major threat to human health, necessitating the identification of new drug targets and lead compounds that are not susceptible to cross-resistance. This study demonstrates that novel reverse thia analogs of the phosphonohydroxamic acid antibiotic fosmidomycin inhibit 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme for Plasmodium falciparum, Escherichia coli, and Mycobacterium tuberculosis that is absent in humans. Some novel analogs with large α-phenyl substituents exhibited strong inhibition across these three DXR orthologues, surpassing the inhibitory activity of fosmidomycin. Despite nanomolar target inhibition, the new DXR inhibitors demonstrated mainly weak or no in vitro growth inhibition of the pathogens. Crystallographic studies revealed that compounds 12a and 12b induce an open PfDXR conformation and that the enzyme selectively binds the S-enantiomers. The study underscores the difficulties of achieving potent cellular activity despite strong DXR inhibition and emphasizes the need for novel structural optimization strategies and comprehensive pharmacokinetic studies.

Cruzipain (CZP) is an essential cysteine protease of Trypanosoma cruzi, the etiological agent of Chagas disease, and a promising druggable target. To date, no CZP inhibitors have reached clinical use, with research efforts mostly hampered by insufficient potency, limited target selectivity or lack of bioactivity translation from the isolated enzyme to the parasite in cellular environments. In this study, we report the design of SH-1, a 1,2,3-triazole-based targeted covalent inhibitor with nanomolar potency (IC₅₀ = 28 nM) and null inhibition of human cathepsin L. SH-1 demonstrates bioactivity translation comparable to that of K777 (1-10 μM), a CZP inhibitor previously advanced to clinical trials. Experimental findings indicate that SH-1 forms a reversible covalent bond with Cys25 in CZP, while in silico and structure-activity relationship studies suggest that this interaction is guided by acid-base equilibrium dynamics. The potential of SH-1 for preclinical development is discussed alongside detailed structure-activity relationships for the further optimization of CZP inhibitors.

A series of novel N-arylsulfonylated C-homoaporphine alkaloids were synthesized under microwave irradiation and evaluated for their in vitro antiplatelet and antimicrobial activities. Among the series, compounds 12a, 12c, 12e, 12f, 12h, 12j, 12k, 12m, and 12o demonstrated highly potent (∼3-fold) platelet aggregation inhibitory activity than acetylsalicylic acid (IC₅₀ = 21.34 μg/mL). Several N-arylsulfonylated C-homoaporphines also exhibited promising antimicrobial activity against various strains, including Macrophoma phaseolina, Trichoderma reesei, and Aspergillus niger, with minimum inhibitory concentrations (MIC) of 12.5, 6.25, and 12.5 μg/mL, respectively, comparable to Ketoconazole [MIC = 12.5 μg/mL (MP and AN strain); 6.25 μg/mL (TR strain)]. 12h showed potent antibacterial activity (IC₅₀ = 6.25 μg/mL against Escherichia coli and Bacillus subtilis) compared to Ampicillin (IC₅₀ = 12.5 μg/mL). After thorough structure-activity relationship (SAR) and in silico studies, C-homoaporphines were identified as a novel class of antiplatelet and antimicrobial agents.

Provided herein are novel ergoline compounds as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating mood disorders such as depressive disorders and bipolar disorders, and processes for preparing such compounds.

Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) is a unique peptidyl-prolyl isomerase (PPIase), and inactivation of Pin1 with a covalent inhibitor is a potential strategy for developing anticancer agents. Herein, a series of sulfolane amino-substituted 2-chloro-5-nitropyrimidine derivatives were disclosed as structurally distinct covalent inhibitors toward Pin1, which were validated for their covalent binding to Cys113 of Pin1 by X-ray cocrystal structures of compounds 4a (IC₅₀ = 11.55 μM) and 6a (IC₅₀ = 3.15 μM). This work provided a new approach for covalent inhibition of Pin1 by taking advantage of the 2-chloro-5-nitropyrimidine as the electrophilic warhead, which might benefit the discovery of potent and drug-like Pin1 inhibitors.

The head-to-tail cyclic peptide cyclo[Arg-Lys-Pro-Tyr-Tle-Leu] (peptide 1, where Tle is l-tert-Leu) has previously been reported to bind to neurotensin receptor 1 (NTS1) (pKi = 5.97). Upon seeking to reproduce this finding, we found that peptide 1 did not have a measurable affinity for NTS1. However, a semipurified preparation of peptide 1 appeared to bind to NTS1 with pKi = 5.83 ± 0.25 SEM. Resynthesis of peptide 1 using a shifted peptide register gave linear and cyclic forms of peptide 1 that were both unable to bind to NTS1. We observe that the previously reported activity of peptide 1 may be due to the presence of high affinity linear contaminants. Approximately 3% contamination with the linear variant would explain the apparent binding of the semipure peptide 1 sample. From this study, we propose that shifting the peptide register during synthesis as a strategy to minimize the presence of potent precursor contaminants.

Dual activation of the TLR7 and TLR8 pathways leads to the production of type I interferon and proinflammatory cytokines, resulting in efficient antigen presentation by dendritic cells to promote T-cell priming and antitumor immunity. We developed a novel series of TLR7/8 dual agonists with varying ratios of TLR7 and TLR8 activity for use as payloads for an antibody-drug conjugate approach. The agonist-induced production of several cytokines in human whole blood confirmed their functional activity. Structure-activity relationship studies guided by structure-based drug design are described.

Recent advancements in pharmaceutical research have focused on developing novel psychoactive compounds and receptor modulators that enhance therapeutic outcomes while minimizing adverse effects. This Patent Highlight examines three innovative approaches: (1) transmucosal delivery of dephosphorylated psychoactive alkaloids, (2) nonhallucinogenic serotonin receptor modulators, and (3) ergoline analogues designed for treating neurological disorders. These innovations offer breakthroughs in drug delivery, receptor targeting, and structural modifications, aiming to address challenges in the treatment of mood disorders, neurological diseases, and chronic pain while improving bioavailability and reducing side effects and hallucinogenic properties.