A hybrid of 1-deoxynojirimycin and benzotriazole induces preferential inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE)

The synthesis of four heterodimers in which the copper(I)-catalysed azide-alkyne cycloaddition was employed to connect a 1-deoxynojirimycin moiety with a benzotriazole scaffold is reported. The heterodimers were investigated as inhibitors against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The heterodimers displayed preferential inhibition (> 9) of BuChE over AChE in the micromolar concentration range (IC50 = 7–50 µM). For the most potent inhibitor of BuChE, Cornish-Bowden plots were used, which demonstrated that it behaves as a mixed inhibitor. Modelling studies of the same inhibitor demonstrated that the benzotriazole and 1-deoxynojirimycin moiety is accommodated in the peripheral anionic site and catalytic anionic site, respectively, of AChE. The binding mode to BuChE was different as the benzotriazole moiety is accommodated in the catalytic anionic site.publishedVersio

1,4-Dideoxy-1,4-imino‑D‑arabinitol (DAB) Analogues Possessing a Hydrazide Imide Moiety as Potent and Selective α‑Mannosidase Inhibitors

The synthesis of two polyhydroxylated pyrrolidines as 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) analogues bearing a hydrazide moiety is described. The DAB analogues act as selective and potent inhibitors of α-mannosidase in the submicromolar concentration ranges (Ki values ranging from 0.23 to 1.4 μM).publishedVersio

Development of tacrine clusters as positively cooperative systems for the inhibition of acetylcholinesterase

The synthesis of four tetra-tacrine clusters where the tacrine binding units are attached to a central scaffold via linkers of variable lengths is described. The multivalent inhibition potencies for the tacrine clusters were investigated for the inhibition of acetylcholinesterase. Two of the tacrine clusters displayed a small but significant multivalent inhibition potency in which the binding affinity of each of the tacrine binding units increased up to 3.2 times when they are connected to the central scaffold.publishedVersio

1,4-Dideoxy-1,4-imino‑D‑arabinitol (DAB) Analogues Possessing a Hydrazide Imide Moiety as Potent and Selective α‑Mannosidase Inhibitors

The synthesis of two polyhydroxylated pyrrolidines as 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) analogues bearing a hydrazide moiety is described. The DAB analogues act as selective and potent inhibitors of α-mannosidase in the submicromolar concentration ranges (Ki values ranging from 0.23 to 1.4 μM)

Investigation of the Enantioselectivity of Acetylcholinesterase and Butyrylcholinesterase upon Inhibition by Tacrine-iminosugar Heterodimers

The copper-catalysed azide-alkyne cycloaddition was applied to prepare three enantiomeric pairs of heterodimers containing a tacrine residue and a 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) or 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) moiety held together via linkers of variable lengths containing a 1,2,3-triazole ring and 3, 4, or 7 CH2 groups. The heterodimers were tested as inhibitors of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE). The enantiomeric heterodimers with the longest linkers exhibited the highest inhibition potencies for AChE (IC50 = 9.7 nM and 11 nM) and BuChE (IC50 = 8.1 nM and 9.1 nM). AChE exhibited the highest enantioselectivity (ca. 4-fold). The enantiomeric pairs of the heterodimers were found to be inactive (GI50 > 100 µM), or to have weak antiproliferative properties (GI50 = 84–97 µM) against a panel of human cancer cells.Gobierno de España PID2020-116460RB-I00, PID2021-123059OB-I00European Commission. Fondo Social Europeo TESIS202001005

Synthesis and Evaluation of the Tetracyclic Ring-System of Isocryptolepine and Regioiso-Mers for Antimalarial, Antiproliferative and Antimicrobial Activities

A series of novel quinoline-based tetracyclic ring-systems were synthesized and evaluated in vitro for their antiplasmodial, antiproliferative and antimicrobial activities. The novel hydroiodide salts 10 and 21 showed the most promising antiplasmodial inhibition, with compound 10 displaying higher selectivity than the employed standards. The antiproliferative assay revealed novel pyridophenanthridine 4b to be significantly more active against human prostate cancer (IC50 = 24 nM) than Puromycin (IC50 = 270 nM) and Doxorubicin (IC50 = 830 nM), which are used for clinical treatment. Pyridocarbazoles 9 was also moderately effective against all the employed cancer cell lines and moreover showed excellent biofilm inhibition (9a: MBIC = 100 µM; 9b: MBIC = 100 µM)