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).     

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.     

Pyrazolo[3,4‐d]pyrimidine Derivatives as COX‐2 Selective Inhibitors: Synthesis and Molecular Modelling Studies

The pyrazolo[3,4‐d]pyrimidine system shows a multitude of interesting pharmacological properties. Owing to the potential anti‐inflammatory activity of 5‐benzamido‐pyrazolo[3,4‐d]pyrimidin‐4‐one derivatives and considering the easy synthesis of this class of compounds, a set of new 5‐benzamido‐1H‐pyrazolo[3,4‐d]pyrimidin‐4‐ones has been prepared in 42‐80% yields by reacting 5‐aminopyrazole‐4(N‐benzoyl)carbohydrazide derivatives and the opportune triethylorthoesters. Compounds 8a , b , 10a – d , and 11a , b revealed a superior inhibitory profile against COX‐2, when compared to that of reference standards NS398 and indomethacin. Molecular modelling studies confirmed the obtained biological results.     

4‐Substituted‐1‐phenyl‐1H‐pyrazolo[3,4‐d]pyrimidine Derivatives: Design,Synthesis, Antitumor and EGFR Tyrosine Kinase Inhibitory Activity

Four series of some 4‐substituted‐1‐phenyl‐1H‐pyrazolo[3,4‐d]pyrimidine derivatives 5a – f , 6a – f , 8a – f , and 9a – f were designed to be screened for their antitumor activity. All compounds were evaluated against breast (MCF‐7) and lung (A‐549) cell lines. Six compounds 5a , 5b , 6b , 6e , 9e , and 9f displaying activity against both cell lines were further estimated for their EGFR‐TK inhibitory activity where they revealed 41–91% inhibition and compound 6b elicited the highest activity (91%). A docking study of these compounds into the ATP‐binding site of EGFR‐TK demonstrated their binding mode where H‐bonding interaction with Met793 through N¹ of pyrimidine or N² of pyrazole was observed.     

Synthesis and antitumor activity of isolongifoleno[7,8‐d]thiazolo[3,2‐a]pyrimidine derivatives via enhancing ROS level

A series of novel isolongifoleno[7,8‐d]thiazolo[3,2‐a]pyrimidine derivatives ( 4a – 4x ) were synthesized from isolongifolanone according fragment‐based design strategy, and their anticancer activity against human aortic smooth muscle cells (HASMC), human breast cancer (MCF‐7) cells, human cervical cancer (HeLa) cells, and human liver cancer (HepG2) cells were investigated. Results of the anticancer activity illustrated that most of the compounds showed potent antitumor activity and compound 4i proved to be the most active derivative with IC₅₀ values of 0.33 ± 0.24 (for MCF‐7 cells), 0.52 ± 0.13 (for HeLa cells), and 3.09 ± 0.11 μM (for HepG2 cells), respectively. Moreover, we assessed the effects of 4i on cell apoptosis, cell cycle distribution, mitochondrial membrane potential, and reactive oxygen species (ROS) generation. The results indicated that compound 4i altered mitochondrial membrane potential and produced ROS leading to cell apoptosis of MCF‐7 cells in a dose‐dependent manner, however, without affecting cell cycle progression. These findings suggested that 4i was an effective compound and provided a promising candidate for anticancer drugs.     

Synthesis,adenosine receptor binding and molecular modelling studies of novel thieno[2,3‐d]pyrimidine derivatives

A series of new molecules containing a thieno[2,3‐d]pyrimidine scaffold was synthesized and characterized by adopting an efficient synthetic scheme. The effect of a free or substituted amino group at 2‐position as well as an oxo‐group, imidazole or 1,2,4‐triazole ring at 4‐position of the scaffold on the affinity and selectivity towards adenosine receptors (ARs) was evaluated. Compounds 17–19 with a free amino group at 2‐position along with the presence of an imidazole/1,2,4‐triazole ring at 4‐position of the scaffold showed selective binding affinities for hA_2A AR, whereas carbamoylation of the amino group at 2‐position (in the presence of an oxo‐group at 4‐position of the scaffold) increased the affinity and selectivity of certain compounds ( 7–10 ) for hA₃ AR. Molecular dynamic simulation study of one of the most active compound 8 (K_i hA₁ > 30 μm , hA_2A = 0.65 μm , and hA₃ = 0.124 μm ) revealed the role of important amino acid residues for imparting good affinity towards hA₃ and hA_2A ARs. Molecular docking studies were carried out for other compounds using the crystal structure of hA_2A AR and a homology model of hA₃ AR to rationalize their structure–activity relationships. The molecular docking results were in agreement with the experimental binding affinity data of ARs.     

Synthesis and Positive Inotropic Evaluation of 2‐(4‐(4‐Substituted benzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)‐acetamides

In an attempt to search for more potent positive inotropic agents, a series of 2‐(4‐(4‐substituted benzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides was synthesized and their positive inotropic activities were evaluated by measuring left atrium stroke volume on isolated rabbit‐heart preparations. Several compounds showed favorable activity compared with the standard drug Milrinone among which 2‐(4‐(4‐(2‐chlorobenzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamide 6e was found to have the most desirable potency with the 6.79 ± 0.18% increased stroke volume (Milrinone: 1.67 ± 0.64%) at a concentration of 1×10^–5 M in our in‐vitro study. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work.     

Both DNA damage and mitochondrial dysfunction are involved in novel oxadiazolo[3,4‐d]pyrimidine nucleoside derivatives‐induced cancer cell death

Eight novel oxdiazolo[3,4‐d]pyrimidine nucleoside derivatives (I‐VIII) were synthesized to investigate their anti‐tumor effects and possible mechanisms. Four human cancer cell lines including Hela, ECA109, HepG2 and A459 cells were used. Compounds VI and VIII showed significant inhibition on cancer cell proliferation by MTT assay and IC₅₀ values were around 30–70 µmol l^?1. Both compounds could release nitric oxide (NO), led to a significant intracellular free Ca²⁺ overloading and resulted in mitochondrial dysfunction, showing a decrease in mitochondrial membrane potential in HepG2 cells in a dose‐dependent manner. Furthermore, compound VIII induced obvious DNA damage on HepG2 cells. These data indicate that compounds VI and VIII are two active antitumor compounds, and both DNA damage and mitochondrial dysfunction are involved in the mechanisms underlying oxadiazolo[3,4‐d]pyrimidine nucleoside derivative‐induced cancer cell death, which might also be related to the released NO. Copyright © 2009 John Wiley & Sons, Ltd.     

Design,synthesis, and biological evaluation of thieno[3,2‐d]pyrimidine derivatives as potential simplified phosphatidylinositol 3‐kinase alpha inhibitors

A series of thieno[3,2‐d]pyrimidine derivatives as phosphatidylinositol 3‐kinase (PI3K) inhibitors was designed using the combination strategy. The synthesis and biological evaluation of the derivatives demonstrated their potent inhibition of PI3K, culminating in the discovery of 7 and 21 . Determination of a co‐crystal structure of 7 complexed with PI3Kα provided the structural basis for the high enzymatic activity. Furthermore, cellular investigation of compounds 7 and 21 revealed that they efficiently suppressed cancer cell lines proliferation through inhibition of intracellular PI3K/AKT/mammalian target of rapamycin pathway. The results provided potent simplified inhibitors of PI3K with a promising overall profile and a chemical series for further optimization to progress into vivo experiments.     

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 and Biological Evaluation of Novel Pyrazoles and Pyrazolo[3,4‐d]pyrimidines Incorporating a Benzenesulfonamide Moiety

Synthesis and biological evaluation of novel pyrazoles and pyrazolo[3,4‐d]pyrimidines are reported. Fourteen compounds were selected by the NCI and tested for their preliminary in‐vitro anticancer activity, whereas all the synthesized compounds were evaluated for their in‐vitro antimicrobial activity. Compound 12a was proven to possess the highest anticancer activity with a broad spectrum profile. It showed particular effectiveness towards leukemia HL‐60 (TB), K‐562, non‐small cell lung cancer NCI‐H23, and colon cancer HT 29, KM 12 cell lines (GI₅₀ = 6.59, 4.44, 1.37, 3.33, and 9.63 μM, respectively). Out of the synthesized compounds, thirteen derivatives were found to display pronounced antimicrobial activity especially against P. aeruginosa. Compounds 2c , 5b , 10 , 11b , 17b , 18b , and 19 were proven to be the most active with a broad spectrum of activity. Compound 19 was found to be equipotent to ampicillin against B. subtilis, whereas compounds 11b and 19 were four times superior to ampicillin against P. aeruginosa, while compounds 5b and 18b were equipotent to ampicillin against the same organism. Moreover, compounds 2c , 10 , and 11b were nearly equipotent to ampicillin against E. coli. On the other hand, compounds 2c , 5b , 10 , 11a , 17b , and 18b exerted nearly half the activity of clotrimazole against C. albicans.     

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.     

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.     

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.     

Synthesis and Evaluation of Biological and Antitumor Activities of Tetrahydrobenzothieno[2,3‐d]Pyrimidine Derivatives as Novel Inhibitors of FGFR1

A series of tetrahydrobenzothieno[2,3‐d]pyrimidine derivatives were designed, synthesized, and evaluated as inhibitors of FGFR1. These analogs were synthesized via Gewald's reaction under mild conditions. The structures of the synthesized compounds were characterized by spectroscopic data (IR, ¹H NMR and MS). Their antitumor activities were evaluated against H460, A549 and U251 cell lines in vitro. Results revealed that the tested compounds showed moderate antitumor activities. Structure–activity relationship analyses indicated that compounds with an aromatic ring substituted in the C‐2 position or with larger molecules such as 3g , 4c , and 7 were more effective than others. The compound, 3g (78.8% FGFR1 inhibition at 10 μ m ), was identified to have the most potent antitumor activities, with IC₅₀ values of 7.7, 18.9, and 13.3 μ m against the H460, A549, and U251 cell lines, respectively. Together, the results suggested that tetrahydrobenzothieno[2,3‐d]pyrimidine derivatives may serve as a potential agent for the treatment of FGFR1‐mediated cancers.     

Synthesis and mycobacterial evaluation of 5‐substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido‐[2,3‐d]pyrimidin‐4(3H)‐one derivatives

5‐Substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido[2,3‐d]pyrimidin‐4(3H)‐one derivatives were synthesized and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus as well as a human monocyte‐derived macrophage (THP‐1), and murine macrophage (RAW 264.7) cell lines to assess their antibacterial and cytotoxic potential, respectively. The compounds showed activity in the range of 1.95–125 µg/ml against M. tuberculosis but showed no activity against M. aurum, E. coli, and S. aureus, indicating selectivity towards slow‐growing mycobacterial pathogens. The compounds exhibited very low to no cytotoxicity up to 500 µg/ml concentration against eukaryotic cell lines. The most potent molecule, 2l , showed a minimum inhibitory concentration of 1.95 µg/ml against M. tuberculosis H37Rv and a selectivity index of >250 against both the eukaryotic cell lines. Furthermore, 2l showed moderate inhibition of whole‐cell mycobacterial drug‐efflux pumps when compared to verapamil, a known potent inhibitor of efflux pumps. Thus, derivative 2l was identified as an antituberculosis hit molecule, which could be used to yield more potent lead molecules.