Synthesis and Positive Inotropic Evaluation of (E)‐2‐(4‐Cinnamylpiperazin‐1‐yl)‐N‐(1‐substituted‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides

A series of (E)‐2‐(4‐cinnamylpiperazin‐1‐yl)‐N‐(1‐substituted‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides were synthesized and evaluated for their positive inotropic activity by measuring the left atrium stroke volume on isolated rabbit heart preparations. This class of compounds presented favorable in vitro activity compared with the standard drug, milrinone, among which N‐(1‐(3‐chlorophenyl)‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)‐2‐(4‐cinnamylpiperazin‐1‐yl)acetamide 5e was found to be the most potent with 16.58 ± 0.11% increased stroke volume (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10^?5 M. The chronotropic effects of the compounds having inotropic effects were also evaluated.     

Synthesis of 2-(4-substitutedbenzyl-[1,4]diazepan-1-yl)-n-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides as inotropic agents

In an attempt to search for more potent positive inotropic agents, a series of N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(substitutedbenzyl-[1,4]diazepan-1-yl)acetamides were synthesized and evaluated for positive inotropic activity by measuring left atrium stroke volume in isolated rabbit heart preparations. Some of these derivatives exhibited favorable activity compared with the standard drug, milrinone, among which 2-(4-(4-methylbenzyl)-[1,4]-diazepan-1-yl)-N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide (6m) was the most potent, increasing stroke volume by 8.38±0.16% (milrinone 2.45± 0.06%) at 3 x 10(-5) m. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work.     

Synthesis and Anticonvulsant Activity of 5‐Phenyl‐[1,2,4]‐triazolo[4,3‐a]quinolines

A series of novel 5‐phenyl‐[1,2,4]‐triazolo[4,3‐a]quinoline derivatives was synthesized by the cyclization of 2‐chloro‐4‐phenyl‐1,2‐dihydronaphthalene with formohydrazide. The starting material 2‐chloro‐4‐phenyl‐1,2‐dihydronaphthalene was synthesized from ethyl‐3‐oxo‐3‐phenylpropanoate and substituted aniline. Their anticonvulsant activities were evaluated by the maximal electroshock (MES) test and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The maximal electroshock test showed that 7‐hexyloxy‐5‐phenyl‐[1,2,4]‐triazolo[4,3‐a]quinoline 4f was found to be the most potent compound with an ED₅₀ value of 6.5 mg/kg and a protective index (PI = ED₅₀ / TD₅₀) value of 35.1, which was much higher than the PI of the reference drug phenytoin.     

Synthesis and Biological Evaluation of [1,2,4]Triazolo[3,4‐a]phthalazine and Tetrazolo[5,1‐a]phthalazine Derivatives Bearing Substituted Benzylpiperazine Moieties as Positive Inotropic Agents

Two series of [1,2,4]triazolo[3,4‐a]phthalazine and tetrazolo[5,1‐a]phthalazine derivatives bearing substituted benzylpiperazine moieties have been synthesized and evaluated for their positive inotropic activity by measuring left atrium stroke volume on isolated rabbit heart preparations. The majority of the derivatives exhibited better in vitro activity than the existing drug, milrinone, and 6‐((4‐(4‐methoxyphenyl)piperazin‐1‐yl)methyl)tetrazolo[5,1‐a]phthalazine. 8 m in particular was identified as the most potent with an increased stroke volume of 12.02 ± 0.20% (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10^–5 m . The chronotropic effects of the compounds that exhibited good potency were also evaluated.     

Fluorinated 1,2,4‐Triazolo[1,5‐a]pyrimidine‐6‐carboxylic Acid Derivatives as Antimycobacterial Agents

A series of fluorinated 1,2,4‐triazolo[1,5‐a]pyrimidine‐6‐carboxylic acid derivatives was designed and synthesized as fluoroquinolone analogues. The synthesized compounds were screened against Mycobacterium tuberculosis H₃₇R_v strain at 6.25 μg/mL concentration. Compound 4 , the 7‐oxo‐2‐(trifluoromethyl)‐4,7‐dihydro‐1,2,4‐triazolo[5,1‐a]pyrimidine‐6‐carboxylic acid was found to be a very potent inhibitor, being able to inhibit 92% growth of M. tuberculosis H₃₇R_v at 6.25 μg/mL concentration. At the same time, it proofed to be nontoxic to mammalian cells (IC₅₀ > 62.5 μg/mL in VERO cells).     

Design and synthesis of 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives as PDE 4B inhibitors endowed with bronchodilator activity

A series of 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives was designed, synthesized, and screened for their phosphodiesterase (PDE 4B) inhibitory activity and bronchodilation ability. Compound 7e showed 41.80% PDE 4B inhibition at 10 µM. Eight compounds were screened for their bronchodilator activity, where compounds 7f and 7e elicited promising bronchodilator activity with EC₅₀ values of 18.6 and 57.1 µM, respectively, compared to theophylline (EC₅₀ = 425 µM). Molecular docking at the PDE 4B active site revealed a binding mode and docking scores comparable to those of a reference ligand, consistent with their PDE 4B inhibition activity.     

Synthesis and Anticonvulsant Activity of 6‐Alkoxy‐[1,2,4]Triazolo[3,4‐a]Phthalazines

A new series of 6‐alkoxy‐[1,2,4]triazolo[3,4‐a]phthalazines ( 3a – 3v ) were synthesized and their anticonvulsant activity and neurotoxicity were evaluated by the maximal electroshock test and the rotarod test respectively. Significant anticonvulsant activity was displayed by a number of compounds. The most promising compounds 6‐(4‐chlorobenzyloxy)‐[1,2,4]triazolo[3,4‐a]phthalazine ( 3f) and 6‐heptyloxy‐[1,2,4]triazolo[3,4‐a]phthalazine ( 3s) showed a median effective dose of 7.1 and 11.0 mg/kg, and had protective index value of 5.2 and 8.0 respectively. The two compounds were further found to have potent activity against seizures induced by pentylenetetrazole, isoniazid, thiosemicarbazide, 3‐mercaptopropionic acid but not seizures induced by strychnine, indicating that the two compounds might function by enhancing gamma‐aminobutyric acid neurotransmission.     

Synthesis and In‐Vitro Anti‐Hepatitis‐B Virus Activity of 6H‐[1]Benzothiopyrano[4,3‐b] quinolin‐10‐ols

A series of 9‐methoxy‐6H‐[1]benzothiopyrano[4,3‐b]quinolin‐10‐ols with a Mannich side chain were synthesized and evaluated for their anti‐Hepatitis B virus (HBV) activity in HepG2.2.15 cells. Some compounds showed significant anti‐HBV activity with IC₅₀ values less than 41 μM. Among them, compound 9b was the most effective anti‐HBV agent (IC₅₀ = 1.7 μM, SI = 60.3).     

Microwave Assistant One Pot Synthesis,Crystal Structure,Antifungal Activities and 3D‐QSAR of Novel 1,2,4‐Triazolo[4,3‐a]pyridines

A series of novel 1,2,4‐triazolo[4,3‐a]pyridines were synthesized, and their structures were characterized by ¹H NMR, MS, elemental analysis, and single‐crystal X‐ray diffraction analysis. The antifungal activities were evaluated. The antifungal activity results indicated that the compound 2b , 2g , 2p , and 2i exhibited good activities. The activity of compound 2b , 2g , 2p , and 2i can compare with the commercial pesticide. The 3D‐QSAR model was developed using CoMFA method. Both the steric and electronic field distributions of CoMFA are in good agreement in this work and will be very helpful in designing a new set of analogues.     

Design,synthesis, and negative inotropic evaluation of 4‐phenyl‐1H‐1,2,4‐triazol‐5(4H)‐one derivatives containing triazole or piperazine moieties

In this study, four novel series of 4‐phenyl‐1H ‐1,2,4‐triazol‐5(4H )‐one derivatives containing triazole or piperazine moieties were designed, synthesized, and evaluated for negative inotropic activity by measuring the left atrium stroke volume in isolated rabbit heart preparations. Almost all of the compounds showed an ability to moderate the cardiac workload by decreasing the heart rate and contractility. Among them, 7h was found to be the most potent with a change in stroke volume of ?48.22 ± 0.36% at a concentration of 3 × 10^?5 mol/L (metoprolol: ?9.74 ± 0.14%). The cytotoxicity of these compounds was evaluated using the human cervical cancer cell line HeLa, the liver cancer cell line Hep3B, and the human normal hepatic cell line LO 2. A preliminary study of the mechanism of action for the compound 7h on the regulation of atrial dynamics with ATP ‐sensitive K⁺ channel and L‐type Ca²⁺ channel blockers glibenclamide and nifedipine was performed in the isolated perfused beating rabbit atria.     

Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines as Selective,Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors

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1-Substituted 4-[Chloropyrazolyl][1,2,4]triazolo[4,3-a]quinoxalines: Synthesis and Structure-Activity Relationships of a New Class of Benzodiazepine and Adenosine Receptor Ligands

Starting from 3-(3-chloro-1H-pyrazol-5-yl)-1H-quinoxalin-2-one ( 2 ) a series of substituted [1,2,4]triazolo[4,3-a]quinoxalines ( 3a-f ) was prepared via a multistep reaction sequence. Affinities of the novel derivatives 3a-f for benzodiazepine as well as for adenosine A₁- and A_2A-receptors of rat brain were determined by radioligand binding assays. 1-Methyl-4-(3-chloro-1H-pyrazol-5-yl) derivative 3a exhibited submicromolar affinity for the benzodiazepine binding site of GABA_A receptors (K_i = 340 nM) and was less potent at A₁- (K_i = 7.85 μM) and A_2A- (K_i = 1.43 μM) adenosine receptors (AR). Derivatives with larger substituents in the 1-position showed reduced binding to benzodiazepine and A_2A-AR, but increased A₁-AR affinity, the 2-thienylmethyl derivative 3f being the most potent and selective A₁-AR ligand of the present series (K_i = 200 nM).     

Novel 3,6‐Disubstituted 7H‐1,2,4‐Triazolo[3,4‐b][1,3,4]thiadiazines: Synthesis,Characterization, and Evaluation of Analgesic / Anti‐inflammatory,Antioxidant Activities

In this study, the synthesis of a new series of 3,6‐disubstituted‐7H‐1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazine 1a – 4c compounds derived from 4‐amino‐3‐substituted‐1,2,4‐triazole‐5‐thiones 1 – 4 is described. All of the synthesized compounds were screened for their possible analgesic / anti‐inflammatory, antioxidant activities and gastric toxicity. The compound 2c was found to have both significant analgesic and consistent anti‐inflammatory activity without inducing any gastric lesions along with minimal lipid peroxidation. A deep insight into the structures of the active compounds revealed that the compounds carrying an electron withdrawing group (a chloride or fluoride) on the phenyl ring at 6‐position of the condensed heterocyclic derivatives exhibited noticeable higher activity.     

Discovery of Novel 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole Derivatives as Potential Anti‐Inflammatory Agents

A novel 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole derivative 5 with good anti‐inflammatory activity was identified from our in‐house library. Based on hit compound 5 , two series of 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole derivative 6a – g and 7a – h were designed and synthesized as novel anti‐inflammatory agents. Most of synthesized compounds exhibited good inhibitory activity on NO and TNF‐α production in LPS‐stimulated RAW 264.7 macrophages, in which the compound 6e showed most potent inhibitory activity on NO (IC₅₀ = 0.86 μm ) and TNF‐α (IC₅₀ = 1.87 μm ) production. Further evaluation revealed that compound 6e displayed more potent in vivo anti‐inflammatory activity than ibuprofen did on xylene‐induced ear oedema in mice. Additionally, Western blot analysis revealed that compound 6e could restore phosphorylation level of IκBα and protein expression of p65 NF‐κB in LPS‐stimulated RAW 264.7 macrophages.     

Design,Synthesis, and Antitumor Activity of (E,Z)‐1‐(dihydrobenzofuran‐5‐yl)‐3‐phenyl‐2‐(1,2,4‐triazol‐1‐yl)‐2‐propen‐1‐ones

A series of (E,Z)‐1‐(dihydrobenzofuran‐5‐yl)‐3‐phenyl‐2‐(1,2,4‐triazol‐1‐yl)‐2‐propen‐1‐ones ( C1 – C35 ) were designed and synthesized, and the structures of compounds (Z)‐ C27 and (Z)‐ C29 were confirmed by single‐crystal X‐ray diffraction. The antitumor activities of these novel compounds against cervical cancer (HeLa), lung cancer (A549), and breast cancer (MCF‐7) cell lines were evaluated in vitro. Majority of the title compounds exhibited strong antitumor activities and were much more promising than the positive control Taxol, which were also accompanied by lower cytotoxicity to normal cells. In particular, compounds (E,Z)‐ C24 exhibited the most consistent potent activities against three neoplastic cells with IC₅₀ values ranging from 3.2 to 7.1 μm . Further researches demonstrated that compounds (E,Z)‐ C24 could induce cell apoptosis and arrest cell cycle at the G2/M and S phases. Meanwhile, the structure–activity relationship between the configurations and cytotoxicity of the compounds was also investigated.     

Synthesis of C‐14‐labeled novel IKK inhibitor: 2‐[14C]‐N‐(6‐chloro‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐3‐pyridinecarboxamide

2‐[¹⁴C]‐N‐(6‐Chloro‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐3‐pyridinecarboxamide (9A , also referred to as [¹⁴C]‐PS‐1145) was synthesized from [¹⁴C]‐paraformaldehyde in five steps in an overall radiochemical yield of 15%. The key intermediate 1‐[¹⁴C]‐6‐chloro‐1,2,3,4‐tetrahydro‐β‐carboline was obtained by Pictet–Spengler cyclization of chlorotryptamine with [¹⁴C]‐paraformaldehyde. Similar reactions were conducted with tryptamine to address the generality of the methodology. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis and calcium channel modulating effects of modified Hantzsch nitrooxyalkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐pyridinecarboxylates

A group of racemic nitrooxyalkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐pyridinecarboxylates 8a–o were synthesized using modified Hantzsch reactions. In vitro calcium channel antagonist activities, determined using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay, showed that compounds 8a–o exhibited weaker calcium antagonist activity (10^–5 to 10^–7 M range) than the reference drug nifedipine (IC₅₀ = 1.43 × 10^–8 M). Compounds 8 possessing a C‐4 R¹ = 2‐pyridyl substituent were always more potent than the approximately equiactive analogs having an R¹ = 3‐pyridyl, 4‐pyridyl or 2‐CF₃‐C₆H₄‐substituent, within each subgroup of nitrooxyalkyl compounds [R² = – (CH₂)_nONO₂ (n = 2, 3, 4) or –CH(CH₂ONO₂)₂]. Although the length of the R² = –(CH₂)_nONO₂ substituent (n = 2–4) was not a determinant of smooth muscle calcium antagonist activity when the C‐4 R¹‐substituent was 2‐pyridyl, when R¹ was a 3‐pyridyl, 4‐pyridyl, or 2‐CF₃‐C₆H₄‐substituent, the relative potency order with respect to the R² = –(CH₂)_nONO₂ substituent was n = 3 and 4 > n = 2. Replacement of the isopropyl substituent of the ester moiety of the calcium antagonist (±)‐2‐pyridyl 3a by a –(CH₂)_nONO₂ (n = 2–4) moiety increased calcium antagonist activity on GPILSM by 8‐fold. In contrast, replacement of the isopropyl substituent of the ester moiety of the calcium agonists (±)‐3‐pyridyl 3b , (±)‐4‐pyridyl 3c or the methyl substituent of the ester moiety of Bay K8644 by a R² nitrooxyalkyl substituent resulted in abolition of their calcium agonist effects on GPILSM that is replaced by a smooth muscle calcium antagonist effect. These calcium antagonist data support the concept that incorporation of a nitrooxyalkyl ester substituent constitutes a valuable drug design strategy to enhance Hantzsch 1,4‐dihydropyridine calcium antagonist and/or abolish calcium agonist effects on smooth muscle. Replacement of the isopropyl ( 8b–c ), or the methyl ( 8d ) group by a –CH₂CH₂ONO₂ moiety resulted in retention of the cardiac positive inotropic effect where the relative potency order with respect to the C‐4 substituent was 2‐CF₃‐C₆H₆‐ (8d) > 3‐pyridyl (8b) ≈ 4‐pyridyl (8c). Model hybrid (calcium channel modulation, ·NO release) compounds, that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4‐dihydropyridine CC modulator that offers a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure–function relationship of calcium channels. Drug Dev. Res. 51:225–232, 2000. © 2001 Wiley‐Liss, Inc.     

The synthesis of [1‐14C]2‐(1H‐tetrazol‐5‐yl)acetic acid

Tetrazoles are a common heterocyclic functionality in many biologically active molecules. [1‐¹⁴C]2‐(1H‐Tetrazol‐5‐yl)acetic acid was required as an intermediate in the synthesis of a development candidate as part of a discovery phase program to complete metabolic profiling studies. [1‐¹⁴C]2‐(1H‐Tetrazol‐5‐yl)acetic acid was prepared in 4 steps overall and in 3 radiochemical steps from K¹⁴CN in an overall 32% radiochemical yield.