Submicromolar Inhibitory Activity Research Articles

Carbonic anhydrase inhibitors. Inhibition of cytosolic isoforms I, II, III, VII and XIII with less investigated inorganic anions

An inhibition study of the cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isoforms I, II, III, VII and XIII with anions such as stannate(IV), selenate(VI), tellurate(VI), perosmate(VIII), persulfate, pyrophosphate(V), pyrovanadate(V), tetraborate, persulfate, perrhenate(VII), perrutenate(VII), selenocyanate, iminodisulfonate, fluorosulfate and trithiocarbonate is reported. Trithiocarbonate was the best inhibitor detected, showing affinities of 8.7–9.9 μM for CA I–III, of 36.15 mM for CA VII and of 0.43 mM for CA XIII. Considering trithiocarbonate as lead, we show that compounds incorporating the new zinc-binding group CS 2 - , such as among other the dithiocarbamates, are even more active inhibitors, with submicromolar inhibitory activity. New classes of CA inhibitors are being detected based on the CS 2 - zinc-binding group.

Bis(sulfonamide) isosters of mycophenolic adenine dinucleotide analogues: Inhibition of inosine monophosphate dehydrogenase

Synthesis of novel inhibitors of human IMP dehydrogenase is described. These inhibitors are isosteric methylenebis(sulfonamide) analogues 5– 8 of earlier reported mycophenolic adenine methylenebis(phosphonate)s 1– 3. The parent bis(phosphonate) 1 and its bis(sulfonamide) analogue 5 showed similar sub-micromolar inhibitory activity against IMPDH2 ( K i ∼ 0.2 μM). However, the bis(sulfonamide) analogues 6 and 8 substituted at the position 2 of adenine were approximately 3- to 10-fold less potent inhibitors of IMPDH2 ( K i = 0.3–0.4 μM) than the corresponding parent bis(phosphonate)s 2 and 3 ( K i = 0.04–0.11μM), respectively.

Synthesis and antioxidant activities of 3,5-dialkoxy-4-hydroxycinnamamides

A series of 3,5-dialkoxy-4-hydroxycinnamamides 6 and 7 was synthesized, and their antioxidant activity was assessed using the thiobarbituric acid reactive substance (TBARS) assay. Interestingly, cinnamamides with longer alkoxy groups on the C-3 and C-5 positions display enhanced inhibition, and most of the compounds in the series tested exhibit excellent lipid peroxidation inhibitory activities. Some cinamamides bearing hexyloxy or 2,6-di-tert-butyl-4-methyl phenol groups have submicromolar inhibitory activities.

Synthesis and biological evaluation of pyrazoline analogues with β-amino acyl group as dipeptidyl peptidase IV inhibitors

A series of pyrazoline derivatives with β-amino acyl group were synthesized and evaluated for their ability to inhibit dipeptidyl peptidase IV. Several pyrazoline derivatives exhibited submicromolar inhibitory activities against DPP-IV. X-ray co-crystal structure of initial hit compound 1h was determined. Among this series, carboxylic acid substituted pyrazoline derivative 2u was the most active and greatly decreased the inhibitory activity toward CYP3A4 enzyme.

In silico design and synthesis of piperazine-1-pyrrolidine-2,5-dione scaffold-based novel malic enzyme inhibitors

Fragment-based virtual library design and virtual screening have been conducted against malic enzyme (ME) homology model. Several scaffolds have been identified as promising motifs to target ME’s NADP binding site. One small focused library has been synthesized and tested against ME. Several compounds from this library have shown sub-micromolar inhibitory activity against malic enzyme.

2-Hydroxy-4,6-diamino-[1,3,5]triazines: A Novel Class of VEGF-R2 (KDR) Tyrosine Kinase Inhibitors

2-Hydroxy-4,6-diamino-[1,3,5]triazines are described which are a novel class of potent inhibitors of the VEGF-R2 (flk-1/KDR) tyrosine kinase. 4-(Benzothiazol-6-ylamino)-6-(benzyl-isopropyl-amino)-[1,3,5]triazin-2-ol (14d) exhibited low nanomolar potency in the in vitro enzyme inhibition assay (IC(50) = 18 nM) and submicromolar inhibitory activity in a KDR-induced MAP kinase autophosphorylation assay in HUVEC cells (IC(50) = 280 nM), and also demonstrated good in vitro selectivity against a panel of growth factor receptor tyrosine kinases. Further, 14d showed antiangiogenic activity in an aortic ring explant assay by blocking endothelial outgrowths in rat aortas with an IC(50) of 1 microM.

Statin‐Derived 1,3‐Oxazinan‐2‐ones as Submicromolar Inhibitors of LFA‐1/ICAM‐1 Interaction: Stabilization of the Metabolically Labile Vanillyl Side Chain.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Statin-derived 1,3-oxazinan-2-ones as submicromolar inhibitors of LFA-1/ICAM-1 interaction: stabilization of the metabolically labile vanillyl side chain

Modification of the vanillyl substituent on a potent, semisynthetic lymphocyte function-associated antigen (LFA)-1/intercellular adhesion molecule (ICAM)-1 binding inhibitor of the statin family resulted in metabolically more stable analogues that displayed submicromolar inhibitory activity in vitro and considerable anti-inflammatory activity in vivo. The benzodioxole derivative 2b emerged with the best overall profile.

Protein Tyrosine Phosphatase 1B Inhibitors: Heterocyclic Carboxylic Acids

Several series of compounds (benzoic acids, pyrazolecarboxylic acids, phenoxyacetic acids, and quinolinoxyacetic acids) were prepared and evaluated for their inhibitory activity against PTP-1B. Several compounds showed submicromolar inhibitory activity.

Synthesis and PTP1B inhibition of 1,2-naphthoquinone derivatives as potent anti-diabetic agents

A new series of 1,2-naphthoquinone derivatives was synthesized by various synthetic methods and evaluated for their ability to inhibit protein tyrosine phosphatase 1B (PTP1B). 1,2-Naphthoquinone derivatives with substituent at R 4 position showed submicromolar inhibitory activity, and compound 24 demonstrated 10- to 60-fold selectivity against the tested phosphatases. Also, several 4-aryl-1,2-naphthoquinone derivatives with substituents at R 3, R 6, R 7, or/and R 8 showed submicromolar inhibitory activity and good plasma stability.

Glutamine-derived aldehydes for the inhibition of human rhinovirus 3C protease

Peptide aldehydes have been synthesized and evaluated as inhibitors of human rhinovirus 3C protease. Those inhibitors containing a C-terminal glutamine aldehyde were prepared using newly developed methodology involving reduction of the corresponding glutarimide, which can be easily prepared from N-protected glutamine. Low molecular weight (<500) compounds with low to submicromolar inhibitory activity in both isolated enzyme and in vitro translation assays have been identified.

The effect of LH-RH-depot and/or flutamide on pituitary, adrenal and testicular hormones in PCA-patients

The clinically used androgen receptor (AR) antagonists (bicalutamide, flutamide and nilutamide) bind with low affinity to AR and can induce escape mechanisms. Furthermore, under AR gene amplification or mutation conditions they demonstrate agonist activity and fail to inhibit AR, causing relapse into castration resistant prostate cancer (CRPC). Discovery of new scaffolds distinct from the 4-cyano/nitro-3-(trifluoromethyl)phenyl group common to currently used antiandrogens is urgently needed to avoid cross-resistance with these compounds. In this study, a series of twenty-nine 7-substituted umbelliferone derivatives was prepared and their antiproliferative activities were evaluated. The most active compound 7a demonstrated submicromolar inhibitory activity in the human prostate cancer cell line (22Rv1); IC50 = 0.93 μM which represents a 50 fold improvement over the clinical antiandrogen bicalutamide (IC50 = 46 μM) and a more than 30 fold improvement over enzalutamide (IC50 = 32 μM). Interestingly, this compound showed even better activity against the human breast cancer cell line (MCF-7); IC50 = 0.47 μM. Molecular modelling studies provided a plausible theoretical explanation for our findings.