Design,synthesis and evaluation of novel quinazoline-2,4-dione derivatives as chitin synthase inhibitors and antifungal agents

A series of novel 1-methyl-3-substituted quinazoline-2,4-dione derivatives were designed, synthesized, and characterized by ¹H NMR, ¹³C NMR and MS spectral data. Their inhibition against chitin synthase (CHS) and antifungal activities were evaluated in vitro. Results showed compounds 5b, 5c, 5e, 5f, 5j, 5k, 5l, and 5o had strong inhibitory potency against CHS. Compound 5c, which has the highest potency among these compounds, had a half-inhibition concentration (IC₅₀) of 0.08 mmol/L, while polyoxin B as positive drug had IC₅₀ of 0.18 mmol/L. These IC₅₀ values of compounds 5i, 5m, 5n, and 5s were greater than 0.75 mmol/L, which revealed that those compounds had weak inhibition activity against CHS. Moreover, most of these compounds exhibited moderate to excellent antifungal activities. In detail, to Candida albicans, the activities of compound 5g and 5k were 8-fold stronger than that of fluconazole and 4-fold stronger than that of polyoxin B; to Aspergillus flavus, the activities of 5g, 5l and 5o were16-fold stronger than that of fluconazole and 8-fold stronger than that of polyoxin B; to Cryptococcus neoformans, the minimum-inhibition-concentration (MIC) values of compounds 5c, 5d, 5e and 5l were comparable to those of fluconazole and polyoxin B. The antifungal activities of these compounds were positively correlated to their IC₅₀ values against CHS. Furthermore, these compounds had negligible actions to bacteria. Therefore, these compounds were promising selective antifungal agents.     

Synthesis and biological evaluation of thiazolidine-2,4-dione and 2,4-thione derivatives as inhibitors of translation initiation

In an effort to generate novel translation initiation inhibitors for cancer therapy, a series of 2'-benzyloxy-5'-substituted-5-benzylidene-thiazolidine-2,4-thione and dione derivatives was synthesized and evaluated for activity in translation initiation specific assays. Several candidates of the 5-benzylidene-thiazolidine-2,4-diones (3c, 3d, and 3f) and -thiones (2b, 2e, and 2j), inhibit cell growth with low microM GI(50) mediated by inhibition of translation initiation, which involves partial depletion of intracellular Ca(2+) stores and strong phosphorylation of eIF2alpha.     

Synthesis of enantiomerically pure perhydro-1,4-diazepine-2,5-dione and 1,4-piperazine-2,5-dione derivatives exhibiting potent activity as apoptosis inhibitors

Apoptosis is the process of programmed cell death and plays a fundamental role in several human diseases. We have previously reported the synthesis of the perhydro-1,4-diazepine-2,5-dione and 1,4-piperazine-2,5-dione derivatives as racemic mixtures. Compounds 1 and 2 showed a potent in vitro and in cellular extracts antiapoptotic activity. In view that the chiral discrimination has been an issue in the development and use of pharmaceutical drugs, the present contribution reports the synthesis of enantiopure peptidomimetics 1 and 2. The biological evaluation of these enantiomers as apoptosis inhibitors is also reported.     

Identification of 2-thioxoimidazolidin-4-one derivatives as novel noncovalent proteasome and immunoproteasome inhibitors

This paper describes the design, synthesis, and biological evaluation of 2-thioxoimidazolidin-4-one derivatives as inhibitors of proteasome and immunoproteasome, potential targets for the treatment of hematological malignancies. In particular, we focused our efforts on the design of noncovalent inhibitors, which might be a promising therapeutic option potentially devoid of drawbacks and side-effects related to irreversible inhibition. Among all the synthesized compounds, we identified a panel of active inhibitors with K_i values towards one or two chymotrypsin-like activities of proteasome (β5c) and immunoproteasome (β5i and β1i subunits) in the low micromolar range. Docking studies suggested a unique binding mode of the molecules in the catalytic site of immunoproteasome proteolytic subunits.     

Liquid chromatographic resolution of 3-amino-1,4-benzodiazepin-2-one derivatives on various Pirkle-type chiral stationary phases

The two enantiomers of N-acyl amide and N-ureide derivatives of 3-amino-5-phenyl-1,4-benzodiazepin-2-ones, which have been known to show anti-respiratory syncytial virus (RSV) activity, were resolved on seven different Pirkle-type chiral stationary phases (CSPs) with the use of 10% isopropyl alcohol in hexane as a mobile phase. Among the seven Pirkle-type CSPs, the one based on (S)-leucine derivative named as N-Phe-L-Leu was found to be most successful, the separation factors (α) and the resolutions (R(S) ) for seven analytes being in the range of 1.78-4.21 and 5.94-15.08, respectively. By resolving N-benzyloxycarbonyl derivatives of 3-amino-5-phenyl(or 5-methyl)-1,4-benzodiazepin-2-ones on Pirkle-type CSPs, the phenyl ring at the 5-position and the N?H hydrogen at the 1-position of analytes were found to play an important role in the chiral recognition.     

Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors

Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (TOP2) mediated DNA damages and causes cellular resistance to clinically used TOP2 poisons. Inhibiting TDP2 can potentially sensitize cancer cells toward TOP2 poisons. Commercial compound P10A10, to which the structure was assigned as 7-phenyl triazolopyrimidine analogue 6a, was previously identified as a TDP2 inhibitor hit in our virtual and fluorescence-based biochemical screening campaign. We report herein that the hit validation through resynthesis and structure elucidation revealed the correct structure of P10A10 (Chembridge ID 7236827) to be the 5-phenyl triazolopyrimidine regioisomer 7a. Subsequent structure–activity relationship (SAR) via the synthesis of a total of 47 analogues of both the 5-phenyl triazolopyrimidine scaffold (7) and its bioisosteric triazolopyridine scaffold (17) identified four derivatives (7a, 17a, 17e, and 17z) with significant TDP2 inhibition (IC₅₀?<?50?µM), with 17z showing excellent cell permeability and no cytotoxicity.     

Synthesis and biological evaluation of pyrido[2,3-d]pyrimidine-2,4-dione derivatives as eEF-2K inhibitors

A small molecule library of pyrido[2,3-d]pyrimidine-2,4-dione derivatives 6–16 was synthesized from 6-amino-1,3-disubstituted uracils 18, characterized, and screened for inhibitory activity against eukaryotic elongation factor-2 kinase (eEF-2K). To understand the binding pocket of eEF-2K, structural modifications of the pyrido[2,3-d]pyrimidine were made at three regions (R¹, R², and R³). A homology model of eEF-2K was created, and compound 6 (A-484954, Abbott laboratories) was docked in the catalytic domain of eEF-2K. Compounds 6 (IC₅₀ = 420 nM) and 9 (IC₅₀ = 930 nM) are found to be better molecules in this preliminary series of pyrido[2,3-d]pyrimidine analogs. eEF-2K activity in MDA-MB-231 breast cancer cells is significantly reduced by compound 6, to a lesser extent by compound 9, and is unaffected by compound 12. Similar inhibitory results are observed when eEF-2K activity is stimulated by 2-deoxy-d-glucose (2-DOG) treatment, suggesting that compounds 6 and 9 are able to inhibit AMPK-mediated activation of eEF-2K to a notable extent. The results of this work will shed light on the further design and optimization of novel pyrido[2,3-d]pyrimidine analogs as eEF-2K inhibitors.     

Identification of 3-acyl-2-phenylamino-1,4-dihydroquinolin-4-one derivatives as inhibitors of the phosphatase SerB653 in Porphyromonas gingivalis, implicated in periodontitis

The serine phosphatase SerB653 plays a crucial role in the infection of Porphyromonas gingivalis, which contributes to the pathogenesis of periodontitis, an inflammatory disease of teeth-supporting tissues. Because functional loss of SerB653 eliminates the virulence of P. gingivalis, SerB653 inhibitors are considered potential periodontitis therapeutic or preventive agents. To identify SerB653 inhibitors with potent anti-periodontitis activity, we conducted a high-throughput screen of a representative 6800-compound subset of a synthetic chemical library of the Korea Chemical Bank (KCB) for compounds with activity against SerB653. The primary screening yielded 150 hits, and subsequent confirmatory studies identified eight compounds, mainly within a single cluster of 3-acyl-2-phenylamino-1,4-dihydroquinolin-4-one derivatives, that showed greater than 50% inhibition of SerB653 activity at a concentration of 50μM. A second screening with a focused library identified 10 compounds with IC(50) values less than 10μM. In antibacterial tests, three of these compounds showed a minimum inhibitory concentration against P. gingivalis growth of 5-50nM.     

Synthesis of novel 1,4-benzoxazin-3-one derivatives as inhibitors against tyrosine kinases

We designed and synthesized a novel 1,4-benzoxazin-3-one derivative 4 which would have inhibitory activities against tyrosine kinases. They could be synthesized easily from various carboxylic acids 10 and commercially available amines using TFP resin without purification. In this article, we will report the design and synthesis of a novel 1,4-benzoxazin-3-one chemical library 4 and the inhibitory activities against KDR and ABL which are closely related to chronic diseases such as cancer.     

Degradations of 4-cholesten-3-one and 1,4-androstadiene-3,17-dione by cholesterol-degrading bacteria

Degradations of 4-cholesten-3-one and 1,4-androstadiene-3,17-dione, which are intermediates of microbial conversion of cholesterol, by cholesterol-degrading bacteria (12 strains of the genus Rhodococcus isolated from food of animal origin and 12 culture collection strains) were examined. All strains had the ability to degrade 4-cholesten-3-one without necessarily being able to degrade cholesterol. On the other hand, the bacteria were divided into three groups with little or no (0-10%), intermediate (10-70%) and high (70-100%) degradation abilities for 1,4-androstadiene-3,17-dione.     

Degradations of 4-cholesten-3-one and 1,4-androstadiene-3,17-dione by cholesterol-degrading bacteria

Degradations of 4-cholesten-3-one and 1,4-androstadiene-3,17-dione, which are intermediates of microbial conversion of cholesterol, by cholesterol-degrading bacteria (12 strains of the genus Rhodococcus isolated from food of animal origin and 12 culture collection strains) were examined. All strains had the ability to degrade 4-cholesten-3-one without necessarily being able to degrade cholesterol. On the other hand, the bacteria were divided into three groups with little or no (0–10%), intermediate (10–70%) and high (70–100%) degradation abilities for 1,4-androstadiene-3,17-dione.     

Design,synthesis, and biological activities of 1-aryl-1,4-diazepan-2-one derivatives as novel triple reuptake inhibitors

A novel series of triple reuptake inhibitors were explored by ligand-based drug design. A cyclic structure was designed from cyclopropane derivative 5 using the core structure of reported monoamine reuptake inhibitors, leading to the formation of the 1-aryl-1,4-diazepan-2-one derivative 23j-S. Compound 23j-S was shown to act as a potent TRI with an excellent ADME-Tox profile. Oral administration of 23j-S significantly enhanced norepinephrine, dopamine, and serotonin levels in the mouse prefrontal cortex and showed significant antidepressant-like activity in tail suspension tests in mouse.     

Synthesis and characterization of gold(III) complexes of 1,4-benzodiazepin-2-ones. Crystal structure of trichloro-[7-chloro-1-(cyclopropylmethyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one]gold(III)

The reaction of gold(III) chloride with several 1,4-benzodiazepin-2-ones, L, gives 1:1 adducts, (L)AuCl₃*, which were characterized by IR, Raman and ¹H NMR spectroscopy. In the title compound the coordination of the ligand, ascertained through a X-ray structure determination, was shown to occur through the 4-nitrogen atom.     

Synthesis and biological evaluation of 1,4-benzodiazepin-2-ones with antitrypanosomal activity

A library of 1,4-benzodiazepines has been synthesized and evaluated against Trypanosoma brucei, a causative parasite of Human African trypanosomiasis. Benzodiazepines possessing a P2- transporter motif were found to have MIC values as low as 0.78 μM.     

Optimization of 1,4-diazepan-2-one containing dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes

Following the discovery of N-acyl-1,4-diazepan-2-one as a novel pharmacophore for potent and selective DPP-4 inhibitors, optimization of this new lead with different substitution on the seven-membered ring resulted in several highly potent and selective, orally bioavailable, and efficacious DPP-4 inhibitors, such as 3R-methyl-1-cyclopropyl-1,4-diazepan-2-one derivative 9i (DPP-4 IC(50)=8.0 nM) and 3R,6R-dimethyl-1,4-diazepan-2-one derivative 14a (DPP-4 IC(50)=9.7 nM).     

Synthesis and biological evaluation of 3-acyl-2-phenylamino-1,4-dihydroquinolin-4(1H)-one derivatives as potential MERS-CoV inhibitors

3-Acyl-2-phenylamino-1,4-dihydroquinolin-4(1H)-one derivatives were synthesized and evaluated to show high anti-MERS-CoV inhibitory activities. Among them, 6,8-difluoro-3-isobutyryl-2-((2,3,4-trifluorophenyl)amino)quinolin-4(1H)-one (6u) exhibits high inhibitory effect (IC₅₀ = 86 nM) and low toxicity (CC₅₀ > 25 μM). Moreover, it shows good metabolic stability, low hERG binding affinity, no cytotoxicity, and good in vivo PK properties.     

1,4-Diazepane-2-ones as novel inhibitors of LFA-1

The design, synthesis, and biological evaluation of 1,4-diazepane-2-ones as novel LFA-1 antagonists from a scaffold-based combinatorial library are described. Initial optimization of the library lead has resulted in high-affinity antagonists of the LFA-1/ICAM-1 interaction, such as compounds 18d and 18e with IC(50) values of 110 and 70 nM, respectively.