Discovery and structure–activity relationship of thienopyridine derivatives as bone anabolic agents

A cell-based assay was performed for the discovery of novel bone anabolic agents. Alkaline phosphatase (ALPase) activity of ST2 cells was utilized as an indicator of osteoblastic differentiation, and thienopyridine derivative 1 was identified as a hit compound. 3-Aminothieno[2,3-b]pyridine-2-carboxamide was confirmed to be a necessary core structure for the enhancement of ALPase activity, and then optimization of the C4-substituent on the thienopyridine ring was carried out. Introduction of cyclic amino groups to the C4-position of the thienopyridine ring improved the activity. Especially, N-phenyl-homopiperazine derivatives were found to be strong enhancers of ALPase among this new series. Furthermore, 3-amino-4-(4-phenyl-1,4-diazepan-1-yl)thieno[2,3-b]pyridine-2-carboxamide (15k) was orally administered to ovariectomized (OVX) rats over 6 weeks for evaluating the effects on areal bone mineral density (aBMD), and statistically significant improvements in aBMD were observed from the dosage of 10 mg/kg/day.     

Identification of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives and their orally active prodrug esters as dual-acting alpha4–beta1 and alpha4–beta7 receptor antagonists

N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives of type 4 were designed to replace the 2,6-dichlorobenzoylamine portion of compound 1 in order to identify novel compounds with improved potency against α4-integrins. Several derivatives were identified as very potent dual-acting α4-integrin, α4β1 and α4β7 antagonists. Investigation of a limited number of prodrug esters led to the discovery of the ethyl ester prodrug 42, which demonstrated good intestinal fluid stability and good permeability. Despite low solubility, 42 gave acceptable blood levels of 30 when dosed orally in non-human primates. Additionally, 42 had an overall excellent profile and was selected for clinical trials. Investigation of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives led to the discovery of several very potent dual-acting α4-integrin antagonists. Ethyl ester prodrug 42 advanced to human clinical trials based on the excellent intestinal fluid stability, good permeability and superior efficacy in non-human primates.     

Synthesis,antituberculosis studies and biological evaluation of new quinoline derivatives carrying 1,2,4-oxadiazole moiety

Tuberculosis is the infectious disease caused by mycobacterium tuberculosis (Mtb), responsible for the utmost number of deaths annually across the world. Herein, twenty-one new substituted 1,2,4-oxadiazol-3-ylmethyl-piperazin-1-yl-quinoline derivatives were designed and synthesized through multistep synthesis followed by in vitro evaluation of their antitubercular potential against Mtb WT H37Rv. The compound QD-18 was found to be promising with MIC value of 0.5?µg/ml and QD-19 to QD-21 were also remarkable with MIC value of 0.25?µg/ml. Additionally, we have carried out experiments to confirm the metabolic stability, cytotoxicity and pharmacokinetics of these compounds along with kill kinetics of QD-18. These compounds were found to be orally bioavailable and highly effective. Altogether, these results indicate that QD-18, QD-19, QD-20 and QD-21 are promising lead compounds for the development of a novel chemical class of antitubercular drugs.     

Novel hybrids of benzothiazole-1,3,4-oxadiazole-4-thiazolidinone: Synthesis,in silico ADME study,molecular docking and in vivo anti-diabetic assessment

A series of new benzothiazole-1,3,4-oxadiazole-4-thiazolidinone hybrid analogs (Tz1-Tz28) were synthesized in search of potential anti-diabetic agents. Molecular docking study was conducted with binding pocket of peroxisome proliferator activated receptor-gamma to elucidate the binding interactions of newly synthesized targets. Seven selected compounds with best docking scores were further screened for in vivo anti-hyperglycemic efficacy by oral glucose tolerance test in non-diabetic rats and on streptozotocin induced diabetic rat models. All the tested compounds demonstrated excellent to moderate reduction in blood glucose levels. Three of the compounds (Tz21, Tz7 and Tz10) showed excellent anti-diabetic effect by reducing concentration of glucose to 157.15 ± 1.79 mg/dL, 154.39 ± 1.71 mg/dL, 167.36 ± 2.45 mg/dL, respectively better than the standard drug, pioglitazone, 178.32 ± 1.88 mg/dL. Moreover, three derivatives Tz21, Tz4 and Tz24 with IC50 values of 0.21 ± 0.01 µM, 9.03 ± 0.12 µM and 11.96 ± 0.40 µM respectively also showed better inhibitory activities on alpha-glucosidase even more than the standard acarbose (IC50 = 18.5 ± 0.20 µM), indicating Tz21 has the highest inhibitory effect among the seven tested derivatives. Prediction of Drug like properties using molinspiration online software suggests that all the synthesized compounds have potential of becoming the orally active molecules. Thus, these novel hybrids could serve as potential candidates to become leads for the development of new drugs eliciting anti-hyperglycemic effect orally.     

Discovery of triazines as potent,selective and orally active PDE4 inhibitors

Expanding on HTS hit 4 afforded a series of [1,3,5]triazine derivatives as novel PDE4 inhibitors. The SAR development and optimization process with the emphasis on ligand efficiency and physicochemical properties led to the discovery of compound 44 as a potent, selective and orally active PDE4 inhibitor.     

Design,synthesis, and bioevaluation of a novel class of (E)-4-oxo-crotonamide derivatives as potent antituberculosis agents

A series of novel (E)-4-oxo-2-crotonamide derivatives were designed and synthesized to find potent antituberculosis agents. All the target compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H₃₇Rv(MTB). Results reveal that 4-phenyl moiety at part A and short methyl group at part C were found to be favorable. Most of the derivatives displayed promising activity against MTB with MIC ranging from 0.125 to 4?µg/mL. Especially, compound IIIa16 was found to have the best activity with MIC of 0.125?μg/mL against MTB and with MIC in the range of 0.05–0.48?µg/mL against drug-resistant clinical MTB isolates.     

Antioxidant activities of 5-hydroxyoxindole and its 3-hydroxy-3-phenacyl derivatives: The suppression of lipid peroxidation and intracellular oxidative stress

The antioxidant activities of 5-hydroxyoxindole (1) and newly synthesized 3,5-dihydroxy-3-phenacyl-2-oxindole derivatives against rat liver microsome/tert-butylhydroperoxide system-induced lipid peroxidation and hydrogen peroxide-induced intracellular oxidative stress were investigated. Compound 1 and its derivatives showed significant suppression of lipid peroxidation and an intracellular oxidative stress. The effects of the more lipophilic derivatives tended to be greater than that of the original compound 1. The cytotoxicity of all of the oxindole derivatives on human promyelocytic leukemia HL60 cells was lower than that of 2,6-di(tert-butyl)-4-hydroxytoluene (BHT), a widely used phenolic antioxidant. These results show that compound 1 and its 3-substituted derivatives could be good lead candidates for future novel antioxidant therapeutics.     

Synthesis of 4-substituted nipecotic acid derivatives and their evaluation as potential GABA uptake inhibitors

In this study, we disclose the design and synthesis of novel 4-susbtituted nipecotic acid derivatives as inhibitors of the GABA transporter mGAT1. Based on molecular modeling studies the compounds are assumed to adopt a binding pose similar to that of the potent mGAT1 inhibitor nipecotic acid. As substitution in 4-position should not cause an energetically unfavorable orientation of nipecotic acid as it is the case for N-substituted derivatives this is expected to lead to highly potent binders. For the synthesis of novel 4-substituted nipecotic acid derivatives a linear synthetic strategy was employed. As a key step, palladium catalyzed cross coupling reactions were used to attach the required biaryl moieties to the ω-position of the alkenyl- or alkynyl spacers of varying length in the 4-position of the nipecotic acid scaffold. The resulting amino acids were characterized with respect to their binding affinities and inhibitory potencies at mGAT1. Though the biological activities found were generally insignificant to poor, two compounds, one of which possesses a reasonable binding affinity for mGAT1, rac-57, the other a notable inhibitory potency at mGAT4, rac-84, both displaying a slight subtype selectivity for the individual transporters, could be identified.     

Synthesis,characterization, in vitro cytotoxicity and antimicrobial investigation and evaluation of physicochemical properties of novel 4-(2-methylacetamide)benzenesulfonamide derivatives

In this study, several sulfonamide derivatives, 4-(2-methylacetylamino)benzenesulfonamides were synthesized. Chemical structures of the derivatives were characterized by ¹H NMR, ¹³C NMR, LC–MS–MS, UV–Vis, FTIR, photoluminescence and elemental analysis. Sulfanilamide was reacted with 2-bromopropionyl bromide, in the presence of pyridine, to form bromo-substituted sulfonamide key intermediates, which were subsequently treated with secondary amines to obtain novel sulfonamide derivatives. All the synthesized compounds were evaluated for in vitro antimicrobial activities and cytotoxicity. Increases in ring size, and rings bearing a nitrogen heteroatom led to improvements in antimicrobial activities. As the presence of CA IX and CA XII enzymes have been implicated in some cancerous tumors, the studies presented herein focuses on targeting these enzymes. It was found that the synthesized derivatives had in vitro anti-cancer properties, where compounds (3–6) were found to be active against all cancerous cells, and no cytotoxic effects on normal cells were observed.     

Natural products-based insecticidal agents 7. Semisynthesis and insecticidal activity of novel 4α-alkyloxy-2-chloropodophyllotoxin derivatives against Mythimna separata Walker in vivo

In continuation of our program aimed at the discovery and development of natural products-based insecticidal agents, 16 novel 4α-alkyloxy-2-chloropodophyllotoxin derivatives were semisynthesized from podophyllotoxin, and preliminarily evaluated for their insecticidal activity against the pre-third-instar larvae of Mythimna separata Walker in vivo. Among all the tested derivatives, especially compounds 4b, 4e, 4g, and 4p exhibited more promising and pronounced insecticidal activity than toosendanin, a commercial insecticide derived from Melia azedarach. Generally, it was obviously demonstrated that the length of straight-chain or branched-chain alkyloxy, and heteroatom-containing cycloalkyloxy at the C-4 position of 2-chloropodophyllotoxin were very important for the insecticidal activity.     

8-Substituted 2-alkynyl-N9-propargyladenines as A2A adenosine receptor antagonists

Structure–activity relationships of 2-alkynyladenine derivatives were explored by varying substituents at the 9-, 8- and 2-positions of the purine moiety in order to optimize A_2A adenosine receptor antagonist activity in vitro. A propargyl group at the 9-position was found to be important for A_2A antagonist activity, and the introduction of a halogen, aryl, or heteroaryl at the 8-position further enhanced activity. A series of 8-substituted 2-alkynyl-N⁹-propargyladenine derivatives exhibited potent antagonist activity, with IC₅₀ values in the low nM range. Compound 4a from this series was found to be orally active at a dose of 3 mg/kg in a mouse catalepsy model and a 6-hydroxydopamine-lesioned rat model of Parkinson’s disease.     

Tricyclic thiazoles are a new class of angiogenesis inhibitors

Tricyclic thiazoleamine derivatives that were identified as hits in a screen against human umbilical vein endothelial cell proliferation were subjected to a structure–activity relationship study. Two structurally superimposable scaffolds—4H-thiochromeno[4,3-d]thiazol-2-amine and 5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-d]thiazol-2-amine derivatives—yielded low-micromolar inhibitors, and two among them 37 and 43 also exhibited antiangiogenic activity in an endothelial tube formation assay. Thus, 37 and 43 can serve as leads to develop a novel class of antiangiogenic agents.     

Discovery of benzimidazole derivatives as orally active renin inhibitors: Optimization of 3,5-disubstituted piperidine to improve pharmacokinetic profile

We previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity. New central cores with carbon side chains were explored to improve potency. We had designed a series of 5-membered azoles and fused heterocycles that interacted with the lipophilic S3 pocket. In the course of modification, renin inhibitory activity was enhanced by the formation of an additional hydrogen bonding with the hydroxyl group of Thr77. Consequently, a series of novel benzimidazole derivatives were discovered as potent and orally bioavailable renin inhibitors. Among those, compound 13 exhibited more than five-fold of plasma renin inhibition than aliskiren in cynomolgus monkeys at dose ratio.     

Synthesis of novel 6-substituted amino-9-(β-d-ribofuranosyl)purine analogs and their bioactivities on human epithelial cancer cells

New nucleoside derivatives with nitrogen substitution at the C-6 position were prepared and screened initially for their in vitro anticancer bioactivity against human epithelial cancer cells (liver Huh7, colon HCT116, breast MCF7) by the NCI-sulforhodamine B assay. N⁶-(4-trifluoromethylphenyl)piperazine analog (27) exhibited promising cytotoxic activity. The compound 27 was more cytotoxic (IC₅₀?=?1–4?μM) than 5-FU, fludarabine on Huh7, HCT116 and MCF7 cell lines. The most potent nucleosides (11, 13, 16, 18, 19, 21, 27, 28) were further screened for their cytotoxicity in hepatocellular cancer cell lines. The compound 27 demonstrated the highest cytotoxic activity against Huh7, Mahlavu and FOCUS cells (IC₅₀?=?1, 3 and 1?μM respectively). Physicochemical properties, drug-likeness, and drug score profiles of the molecules showed that they are estimated to be orally bioavailable. The results pointed that the novel derivatives would be potential drug candidates.     

Design,synthesis and biological evaluation of novel pyrimidinedione derivatives as DPP-4 inhibitors

A series of novel pyrimidinedione derivatives were designed and evaluated for in vitro dipeptidyl peptidase-4 (DPP-4) inhibitory activity and in vivo anti-hyperglycemic efficacy. Among them, the representative compounds 11, 15 and 16 showed excellent inhibitory activity of DPP-4 with IC₅₀ values of 64.47?nM, 188.7?nM and 65.36?nM, respectively. Further studies revealed that compound 11 was potent in vivo hypoglycemic effect. The structure–activity relationships of these pyrimidinedione derivatives had been discussed, which would be useful for developing novel DPP-4 inhibitors as treating type 2 diabetes.     

Synthesis and structure–activity relationship of fused-pyrimidine derivatives as a series of novel GPR119 agonists

A series of fused-pyrimidine derivatives have been discovered as potent and orally active GPR119 agonists. A combination of the fused-pyrimidine structure and 4-chloro-2,5-difluorophenyl group provided the 5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide derivative 14a as a highly potent GPR119 agonist. Further optimization of the amino group at the 4-position in the pyrimidine ring led to the identification of 2-{1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl}acetamide (16b) as an advanced analog. Compound 16b was found to have extremely potent agonistic activity and improved glucose tolerance at 0.1 mg/kg po in mice. We consider compound 16b and its analogs to have clear utility in exploring the practicality of GPR119 agonists as potential therapeutic agents for the treatment of type 2 diabetes mellitus.     

Synthesis and bioactive evaluation of a novel series of coumarinazoles

A series of novel coumarinazoles were designed, synthesized, and characterized by IR, NMR, MS and HRMS spectra. The bioactive assay for the newly prepared compounds against six bacteria and five fungi manifested that most new compounds exhibited good or even stronger antibacterial and antifungal activities in comparison with reference drugs Chloromycin, Norfloxacin and Fluconazole. Bis-azole alcohols 7a and 7d–e showed better anti-Candida utilis activity than mono-azole derivatives 4a and 4d–e at the tested concentrations, and they were more potent than the clinical Fluconazole. While triazole alcohol 7a gave comparable anti-Candida albicans and anti-Candida mycoderma activity to Fluconazole and better anti-MRSA activity than mono-triazole one 4a and clinical Norfloxacin. 1H-Benzoimidazol-2-ylthio coumarin derivatives 4e and 7e gave the strongest anti-Escherichia coli JM109 efficacy. Oxiran-2-ylmethoxy moiety was found to be a beneficial fragment to improve antibacterial and antifungal activity to some extent.     

Discovery and structure–activity relationships of a novel series of benzopyran-based KATP openers for urge urinary incontinence

A novel series of benzopyran derivatives were synthesized and evaluated as K_ATP channel openers. Structure–activity relationships were investigated around 4-position of the benzopyran nucleus. Optimization of 4-substituent with some heterocyclic rings led to compound 13b bearing a benzo[d]isoxazol-3-one moiety as a potent and selective K_ATP channel opener in vitro. In two anesthetized rat models of myogenic bladder overactivity, compound 13b was found to inhibit spontaneous bladder contractions.     

Syntheses and bioactivities of songorine derivatives as novel G protein-coupled receptor antagonists

Songorine isolated from Aconitum brachypodum Diels possesses prominent activity of inhibiting G protein-coupled receptors (GPCRs) in the early screening process. In this paper, a series of Songorine derivatives were synthesized and their inhibitory activities on GPCRs were also evaluated by using the Double Antibody Sandwich ELISA (DAS-ELISA) in vitro. Among them, three derivatives (3a, 4, 7) exhibited significant inhibitory activity against GPCRs with IC₅₀ values of 0.08–0.29?nM. Moreover, the structure-activity relationships (SARs) of songorine derivatives were discussed in detail. They have great potentials as novel GPCRs antagonists in the future.     

Thiazolo[3,2-a]benzimidazol-3(2H)-one derivatives: Structure–activity relationships of selective nucleotide pyrophosphatase/phosphodiesterase1 (NPP1) inhibitors

Ecto-nucleotide pyrophosphatase/phosphodiesterase1 (NPP1) is the most important member of the NPP family, which consists of seven closely related proteins (NPP1–NPP7). This glycoprotein is a membrane-associated or secreted enzyme, which catalyzes the hydrolysis of a wide range of phosphodiester bonds, e.g., in nucleoside triphosphates, dinucleotides and nucleotide sugars. NPP1 plays a crucial role in various physiological functions including bone mineralization, soft-tissue calcification, and insulin receptor signaling. Recently, an upregulated expression of NPP1 has been observed in astrocytic brain cancers. Therefore, NPP1 has been proposed as a novel drug target for the treatment of glioblastoma. Despite their therapeutic potential, only few NPP1 inhibitors have been reported to date, which are in most cases non- or only moderately selective. The best investigated NPP1 inhibitors so far are nucleotide derivatives and analogs, however they are not orally bioavailable due to their high polarity. We identified thiazolo[3,2-a]benzimidazol-3(2H)-one derivatives as a new class of NPP1 inhibitors with drug-like properties. Among the 25 derivatives investigated in the present study, 2-[(5-iodo-2-furanyl)methylene]thiazolo[3,2-a]benzimidazol-3(2H)-one (17) was found to be the most potent NPP1 inhibitor with a K_i value of 467 nM versus ATP as a substrate and an un-competitive mechanism of inhibition. Compound 17 did not inhibit other human ecto-nucleotidases, including NTPDase1 (CD39), NTPDases2-3, NPP2, NPP3, tissue-nonspecific alkaline phosphatase (TNAP), and ecto-5′-nucleotidase (eN, CD73), and is thus highly selective for NPP1.