- Synthesis and screening of triazolopyrimidine scaffold as multi-functional agents for Alzheimer's disease therapies
-
In present study a series of triazolopyrimidine-quinoline and cyanopyridine-quinoline hybrids were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs). Molecular docking and scoring was utilized for the design of inhibitors. The molecules were synthesized via an easily accessible, convergent synthetic route. Three triazolopyrimidine based compounds showed nanomolar activity towards acetylcholinesterase. Among them, Ethyl 6-fluoro-4-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)quinoline-3-carboxylate (10d), strongly inhibited AChE with IC50 value of 42 nM. Furthermore compound 10d was identified as most promising compound with 12 fold selectivity against butyrylcholinesterase (BuChE). This compound displayed a composed multitargeted profile with promising inhibition of self-induced and AChE - induced Aβ aggregation and antioxidant activity.
- Kumar, Jitendra,Meena, Poonam,Singh, Anju,Jameel, Ehtesham,Maqbool, Mudasir,Mobashir, Mohammad,Shandilya, Ashutosh,Tiwari, Manisha,Hoda, Nasimul,Jayaram
-
-
Read Online
- Crystal Packing Modulation of the Strength of Resonance-Assisted Hydrogen Bonds and the Role of Resonance-Assisted Pseudoring Stacking in Geminal Amido Esters: Study Based on Crystallography and Theoretical Calculations
-
A detailed experimental and theoretical investigation of a series of substituted geminal amido esters (ethyl (2E)-3-(arylamino)-2-(arylcarbamoyl)prop-2-enoate, AME-1-8) leading to the identification of a unique angularly fused pseudotricyclic (S(6),S(6),S(6)) ring system stabilized by an intramolecular resonance-assisted hydrogen bond (RAHB) and a non-RAHB are presented in addition to weak intermolecular interactions. An analysis of X-ray and theoretical models reveals that the strength of the intramolecular RAHB (N1-H1N···O1) varies in a wide range (6.9-11.4 kcal mol-1) due to crystal-packing constraints arising from different aromatic ring substitutions. However, the effect is less significant and the strength differs only in a narrow range (8.2-9.9 kcal mol-1) in the case of non-RAHB. The downfield shift (δ~12.3) observed for the N-Haniline signal in 1H NMR spectra of AME-1-8 is due to the presence of intramolecular RAHB. A PIXEL energy analysis suggests that the molecular dimer formed by stacking of RAHB pseudorings is found to be strong (Etot = -14.4 to -17.9 kcal mol-1), and this dimer forms the basic motif in most of the structures reported herein. A detailed analysis of the isostructurality suggests that the basic motif exists in most of the structural combinations. The weak intermolecular C-H···O, C-H···Cl, and C-H···πinteractions play a vital role in the stabilization of these crystal structures, as evaluated by PIXEL and Bader's quantum theory of atoms in molecules approach (QTAIM). A lattice energy analysis suggests that the Coulombic contribution and total lattice energies are higher in the para-substituted compounds (AME-2, AME-5, and AME-8) in comparison to the other isomeric compounds. Further, the crystal packing of these compounds is analyzed on the basis of the energy frameworks. It shows that most of the crystals show similar 3D topologies, suggesting that these compounds may have similar mechanical behavior.
- Venkatesan, Perumal,Thamotharan, Subbiah,Percino, M. Judith,Ilangovan, Andivelu
-
p. 779 - 798
(2021/01/13)
-
- Quinoline carboxamide core moiety-based compounds inhibit P. falciparum falcipain-2: Design, synthesis and antimalarial efficacy studies
-
Targeting Falcipain-2 (FP2) for the development of antimalarials is a promising and established concept in antimalarial drug discovery and development. FP2, a member of papain-family cysteine protease of the malaria parasite Plasmodium falciparum holds an important role in hemoglobin degradation pathway. A new series of quinoline carboxamide-based compounds was designed, synthesized and evaluated for antimalarial activity. We integrated molecular hybridization strategy with in-silico drug design to develop FP2 inhibitors. In-vitro results of FP2 inhibition by Qs17, Qs18, Qs20 and Qs21 were found to be in low micromolar range with IC50 4.78, 7.37, 2.14 and 2.64 μM, respectively. Among the 25 synthesized compounds, four compounds showed significant antimalarial activities. These compounds also depicted morphological and food-vacuole abnormalities much better than that of E-64, an established FP2 inhibitor. Overall these aromatic substituted quinoline carboxamides can serve as promising leads for the development of novel antimalarial agents.
- Singh, Anju,Kalamuddin, Md,Maqbool, Mudasir,Mohmmed, Asif,Malhotra, Pawan,Hoda, Nasimul
-
supporting information
(2020/12/07)
-
- Sulfonamide-based 4-anilinoquinoline derivatives as novel dual Aurora kinase (AURKA/B) inhibitors: Synthesis, biological evaluation and in silico insights
-
Aurora kinases (AURKs) were identified as promising druggable targets for targeted cancer therapy. Aiming at the development of novel chemotype of dual AURKA/B inhibitors, herein we report the design and synthesis of three series of 4-anilinoquinoline derivatives bearing a sulfonamide moiety (5a-d, 9a-d and 11a-d). The percent inhibition of AURKA/B was determined for all target quinolines, then compounds showed more than 50percent inhibition on either of the enzymes, were evaluated further for their IC50 on the corresponding enzyme. In particular, compound 9d displayed potent AURKA/B inhibitory activities with IC50 of 0.93 and 0.09 μM, respectively. Also, 9d emerged as the most efficient anti-proliferative analogue in the US-NCI anticancer assay toward the NCI 60 cell lines panel, with broad spectrum activity against different cell lines from diverse cancer subpanels. Docking studies, confirmed that, the sulfonamide SO2 oxygen was involved in a hydrogen bond with Lys162 and Lys122 in AURKA and AURKB, respectively, whereas, the sulfonamide NH could catch hydrogen bond interaction with the surrounding amino acid residues Lys141, Glu260, and Asn261 in AURKA and Lys101, Glu177, and Asp234 in AURKB. Furthermore, N1 nitrogen of the quinoline scaffold formed an essential hydrogen bond with the hinge region key amino acids Ala213 and Ala173 in AURKA and AURKB, respectively.
- Abdelgawad, Mohamed A.,Al-Sanea, Mohammad M.,Alharbi, Khalid S.,Ali Farahat, Ibrahim,Alzarea, Abdulaziz I.,Alzarea, Sami I.,Bakr, Rania B,El Kerdawy, Ahmed M.,Eldehna, Wagdy M.,Elkamhawy, Ahmed,Elshemy, Heba A. H.,Joo Roh, Eun,Lee, Kyeong,Paik, Sora,Syed Nasir Abbas, Bukhari
-
-
- Design, synthesis, in vitro and in silico studies of novel 4-oxoquinoline ribonucleoside derivatives as HIV-1 reverse transcriptase inhibitors
-
Human immunodeficiency virus type 1 (HIV-1) is a public health problem that affects over 38 million people worldwide. Although there are highly active antiretroviral therapies, emergence of antiviral resistant strains is a problem which leads to almost a million death annually. Thus, the development of new drugs is necessary. The viral enzyme reverse transcriptase (RT) represents a validated therapeutic target. Because the oxoquinolinic scaffold has substantial biological activities, including antiretroviral, a new series of 4-oxoquinoline ribonucleoside derivatives obtained by molecular hybridization were studied here. All synthesized compounds were tested against human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT), and 9a and 9d displayed the highest antiviral activities, with IC50 values of 1.4 and 1.6 μM, respectively. These compounds were less cytotoxic than AZT and showed CC50 values of 1486 and 1394 μM, respectively. Molecular docking studies showed that the most active compounds bound to the allosteric site of the enzyme, suggesting a low susceptibility to the development of antiviral resistance. In silico pharmacokinetic and toxicological evaluations reinforced the potential of the active compounds as anti-HIV candidates for further exploration. Overall, this work showed that compounds 9a and 9d are promising scaffold for future anti-HIV-1 RT drug design.
- Forezi, Luana da S.M.,Ribeiro, Mariana M.J.,Marttorelli, Andressa,Abrantes, Juliana L.,Rodrigues, Carlos R.,Castro, Helena Carla,Souza, Thiago Moreno L.,Boechat, Fernanda da C.S.,de Souza, Alessandra M.T.,de Souza, Maria Cecília B.V.
-
-
- 3-(Benzo[: D] thiazol-2-yl)-4-aminoquinoline derivatives as novel scaffold topoisomerase i inhibitor via DNA intercalation: Design, synthesis, and antitumor activities
-
Twenty-seven 3-(benzo[d]thiazol-2-yl)-4-aminoquinoline derivatives have been designed and synthesized as topoisomerase I inhibitors. The in vitro anti-proliferation evaluation against four human cancer cell lines (MGC-803, HepG-2, T24, and NCI-H460) and one normal cell line (HL-7702) indicated that most of them exhibited potent cytotoxicity. Among them, 5a was identified as the most promising candidate with a low IC50 value of about 2.20 ± 0.14 and was selected for further exploration. Spectroscopic analyses and agarose-gel electrophoresis assays indicated that 5a could interact with DNA and strongly inhibit topoisomerase I (Topo I). Further screening of the Topo I activity of compounds 5b, 5c, 5e, 5f, 5h, 5i, 5j, 5l, and 5n suggested that some of the compounds might exert quite a different cytotoxicity profile to that of 5a. Molecular modeling studies confirmed that 5a adopts a unique mode to interact with DNA and Topo I. Other molecular mechanistic studies suggested that the treatment of MGC-803 cells with 5a induces S phase arrest, up-regulates the pro-apoptotic protein, down-regulates the anti-apoptotic protein, activates caspase-3, and subsequently induces mitochondrial dysfunction so as to induce cell apoptosis. The in vivo efficiency of 5a was also evaluated on MGC-803 xenograft nude mice and the relative tumor growth inhibition was 42.4percent at 12 mg kg-1 without an obvious loss in the body weight. This journal is
- Chen, Nan-Ying,Gu, Zi-Yu,Li, Xiao-Juan,Liao, Hao-Ran,Mo, Dong-Liang,Pan, Cheng-Xue,Su, Gui-Fa,Yuan, Jing-Mei,Zhang, Guo-Hai
-
p. 11203 - 11214
(2020/07/15)
-
- Structural development of a type-1 ryanodine receptor (RyR1) Ca2+-release channel inhibitor guided by endoplasmic reticulum Ca2+ assay
-
Type-1 ryanodine receptor (RyR1) is a calcium-release channel localized on sarcoplasmic reticulum (SR) of the skeletal muscle, and mediates muscle contraction by releasing Ca2+ from the SR. Genetic mutations of RyR1 are associated with skeletal muscle diseases such as malignant hyperthermia and central core diseases, in which over-activation of RyR1 causes leakage of Ca2+ from the SR. We recently developed an efficient high-throughput screening system based on the measurement of Ca2+ in endoplasmic reticulum, and used it to identify oxolinic acid (1) as a novel RyR1 channel inhibitor. Here, we designed and synthesized a series of quinolone derivatives based on 1 as a lead compound. Derivatives bearing a long alkyl chain at the nitrogen atom of the quinolone ring and having a suitable substituent at the 7-position of quinolone exhibited potent RyR1 channel-inhibitory activity. Among the synthesized compounds, 14h showed more potent activity than dantrolene, a known RyR1 inhibitor, and exhibited high RyR1 selectivity over RyR2 and RyR3. These compounds may be promising leads for clinically applicable RyR1 channel inhibitors.
- Mori, Shuichi,Iinuma, Hiroto,Manaka, Noriaki,Ishigami-Yuasa, Mari,Murayama, Takashi,Nishijima, Yoshiaki,Sakurai, Akiko,Arai, Ryota,Kurebayashi, Nagomi,Sakurai, Takashi,Kagechika, Hiroyuki
-
p. 837 - 848
(2019/07/12)
-
- A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo[3,4-b]pyridine derivatives against Alzheimer's disease
-
2-(piperazin-1-yl)–N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides are described as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and amyloid β aggregation inhibitors. Formation of synthesized compounds (P1–P9) was justified via H1 NMR, C13 NMR, mass spectra and single crystal X-Ray diffraction study. All compounds were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activity, inhibition of self-mediated Aβ aggregation and Cu(II)-mediated Aβ aggregation. Also, docking study carried out was in concordance with in vitro results. The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity (IC50 = 4.8 nM). Kinetic study of P3 suggested it to be a mixed type inhibitor. In vitro study revealed that all the compounds are capable of inhibiting self-induced β-amyloid (Aβ) aggregation with the highest inhibition percentage to be 81.65%. Potency of P1 and P3 to inhibit self-induced Aβ1-42 aggregation was ascertained by TEM analysis. Compounds were also evaluated for their Aβ disaggregation, antioxidation, metal-chelation activity.
- Umar, Tarana,Shalini, Shruti,Raza, Md Kausar,Gusain, Siddharth,Kumar, Jitendra,Seth, Prerna,Tiwari, Manisha,Hoda, Nasimul
-
-
- Synthesis and biological evaluation of novel 3-(quinolin-4-ylamino)benzenesulfonamidesAQ3 as carbonic anhydrase isoforms I and II inhibitors
-
Carbonic anhydrases (CAs, EC 4.2.1.1) are crucial metalloenzymes that are involved in diverse bioprocesses. We report the synthesis and biological evaluation of novel series of benzenesulfonamides incorporating un/substituted ethyl quinoline-3-carboxylate moieties. The newly synthesised compounds were in vitro evaluated as inhibitors of the cytosolic human (h) isoforms hCA I and II. Both isoforms hCA I and II were inhibited by the quinolines reported here in variable degrees: hCA I was inhibited with KIs in the range of 0.966–9.091 μM, whereas hCA II in the range of 0.083–3.594 μM. The primary 7-chloro-6-flouro substituted sulphfonamide derivative 6e (KI = 0.083 μM) proved to be the most active quinoline in inhibiting hCA II, whereas, its secondary sulfonamide analog failed to inhibit the hCA II up to 10 μM, confirming the crucial role of the primary sulphfonamide group, as a zinc-binding group for CA inhibitory activity.
- Al-Sanea, Mohammad M.,Elkamhawy, Ahmed,Paik, Sora,Bua, Silvia,Ha Lee, So,Abdelgawad, Mohamed A.,Roh, Eun Joo,Eldehna, Wagdy M.,Supuran, Claudiu T.
-
p. 1457 - 1464
(2019/08/26)
-
- Synthesis and pharmacological evaluation of pyrazolo[4,3-c]quinolinones as high affinity GABAA-R ligands and potential anxiolytics
-
The synthesis, in vitro ligand binding study and in vivo Elevated Plus Maze test (EPM) of a series of pyrazolo[4,3-c]quinolin-3-ones (PQs) are reported. Multistep synthesis of PQs started from anilines and diethyl 2-(ethoxymethylene)malonate to give the q
- López Rivilli, Marisa J.,Turina, Anahí V.,Bignante, Elena A.,Molina, Victor H.,Perillo, María A.,Bri?on, Margarita C.,Moyano, Elizabeth L.
-
p. 3967 - 3974
(2018/06/29)
-
- Organocatalytic activation of isocyanides: N-heterocyclic carbene-catalyzed enaminone synthesis from ketones
-
The first example of the use of an N-heterocyclic carbene (NHC) as an organocatalyst for the activation of isocyanides was demonstrated. On the basis of previous reports on the interaction between NHCs and isocyanides, we developed a catalytic cycle invol
- Kim, Jungwon,Hong, Soon Hyeok
-
p. 2401 - 2406
(2017/03/11)
-
- 6-substituted-1-((1-substituted phenyl-1,2,3-triazole-4-yl)methyl)-4-carbonylquinoline-3-ethyl formate compound, and preparation and application thereof
-
The invention specifically discloses a 6-substituted-1-((1-substituted phenyl-1,2,3-triazole-4-yl)methyl)-4-carbonylquinoline-3-ethyl formate compound, and preparation and application thereof, belonging to the technical field of organic synthesis. The com
- -
-
Paragraph 0049; 0050; 0080
(2016/10/07)
-
- 6-substituted-1-((1-substituted phenyl-1,2,3-triazole-4-yl)methyl)-4-carbonylquinoline-3-carboxylic acid or pharmaceutical salt, preparation and application
-
The present invention belongs to the technical field of organic synthesis, and specifically discloses 6-substituted-1-((1-substituted phenyl-1,2,3-triazole-4-yl)methyl)-4-carbonylquinoline-3-carboxylic compounds or a pharmaceutical salt thereof, and prepa
- -
-
Paragraph 0052; 0053; 0062
(2017/01/23)
-
- Protozoan Parasite Growth Inhibitors Discovered by Cross-Screening Yield Potent Scaffolds for Lead Discovery
-
Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (1) as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs against other protozoal species: T. cruzi (Chagas disease), Leishmania major (cutaneous leishmaniasis), and Plasmodium falciparum (malaria). Based on hits identified in this screening campaign, we describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors' biological activities against these parasites. In doing this, we have identified several potent proliferation inhibitors for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile (NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine (NEU-1017, 68) for L. major and P. falciparum.
- Devine, William,Woodring, Jennifer L.,Swaminathan, Uma,Amata, Emanuele,Patel, Gautam,Erath, Jessey,Roncal, Norma E.,Lee, Patricia J.,Leed, Susan E.,Rodriguez, Ana,Mensa-Wilmot, Kojo,Sciotti, Richard J.,Pollastri, Michael P.
-
supporting information
p. 5522 - 5537
(2015/08/03)
-
- Invariant and variable intermolecular interactions in functionalized malonic acid half-esters: X-ray, Hirshfeld surface and PIXEL energy analyses
-
A series of functionalized malonic acid half-ester derivatives (parent compound MHE-1), with variations in functional groups at different positions on the aromatic ring, have been synthesized and crystal structures are determined at room temperature (296
- Venkatesan, Perumal,Thamotharan, Subbiah,Kumar, Rajendran Ganesh,Ilangovan, Andivelu
-
p. 904 - 915
(2015/02/19)
-
- Synthesis and biological evaluation of 4-oxoquinoline-3-carboxamides derivatives as potent anti-fibrosis agents
-
Thirty-one 4-oxoquinoline-3-carboxamides derivatives were synthesized and evaluated for their anti-fibrotic activities by the inhibition of TGF-β1-induced total collagen accumulation and anti-inflammatory activities by the inhibition of LPS-stimulated TNF-α production. Among them, three compounds (10a, 10l and 11g) exhibited potent inhibitory effects on both TGF-β1-induced total collagen accumulation and LPS-stimulated TNF-α production. Furthermore, oral administrations of 10l at a dose of 20 mg/kg/day for 4 weeks effectively alleviated lung inflammation and injury, and decreased lung collagen accumulation in bleomycin-induced pulmonary fibrosis model. Histopathological evaluation of lung tissue confirmed 10l as a potential, orally active agent for the treatment of pulmonary fibrosis.
- Zhu, Jun,He, Lin,Ma, Liang,Wei, Zhe,He, Jiqiang,Yang, Zhuang,Pu, Yuzhi,Cao, Dong,Wu, Yuzhe,Xiang, Mingli,Peng, Aihua,Wei, Yuquan,Chen, Lijuan
-
supporting information
p. 5666 - 5670
(2015/01/08)
-
- Synthesis and biological evaluation of a class of quinolone triazoles as potential antimicrobial agents and their interactions with calf thymus DNA
-
A novel series of quinolone triazoles were synthesized and characterized by IR, NMR, MS and HRMS spectra. All the newly prepared compounds were screened for their antimicrobial activities against seven bacteria and four fungi. Bioactive assay manifested that most of new compounds exhibited good or even stronger antibacterial and antifungal activities against the tested strains including multi-drug resistant MRSA in comparison with reference drugs Norfloxacin, Chloromycin and Fluconazole. The preliminary interactive investigations of compound 6b with calf thymus DNA by fluorescence and UV-vis spectroscopic methods revealed that compound 6b could effectively intercalate DNA to form compound 6b-DNA complex which might block DNA replication and thus exert its antimicrobial activities.
- Cui, Sheng-Feng,Ren, Yu,Zhang, Shao-Lin,Peng, Xin-Mei,Damu, Guri L.V.,Geng, Rong-Xia,Zhou, Cheng-He
-
p. 3267 - 3272
(2013/06/27)
-
- Further studies on bis-charged tetraazacyclophanes as potent inhibitors of small conductance Ca2+-activated K+ channels
-
Previously, quinolinium-based tetraazacyclophanes, such as UCL 1684 and UCL 1848, have been shown to be extraordinarily sensitive to changes in chemical structure (especially to the size of the cyclophane system) with respect to activity as potent non-peptidic blockers of the small conductance Ca 2+-activated K+ ion channels (SKCa). The present work has sought to optimize the structure of the linking chains in UCL 1848. We report the synthesis and SKCa channel-blocking activity of 29 analogues of UCL 1848 in which the central CH2 of UCL 1848 is replaced by other groups X or Y = O, S, CF2, CO, CHOH, CC, CHCH, CHMe to explore whether subtle changes in bond length or flexibility can improve potency still further. The possibility of improving potency by introducing ring substituents has also been explored by synthesizing and testing 25 analogues of UCL 1684 and UCL 1848 with substituents (NO2, NH2, CF 3, F, Cl, CH3, OCH3, OCF3, OH) in the 5, 6 or 7 positions of the aminoquinolinium rings. As in our earlier work, each compound was assayed for inhibition of the afterhyperpolarization (AHP) in rat sympathetic neurons, an action mediated by the SK3 subtype of the SK Ca channel. One of the new compounds (39, R7 = Cl, UCL 2053) is twice as potent as UCL 1848 and UCL 1684: seven are comparable in activity.
- Yang, Donglai,Arifhodzic, Lejla,Ganellin, C. Robin,Jenkinson, Donald H.
-
p. 907 - 923
(2013/07/27)
-
- Molecular design, synthesis and biological evaluation of 1,4-dihydro-4-oxoquinoline ribonucleosides as TcGAPDH inhibitors with trypanocidal activity
-
The 1,4-dihydro-4-oxoquinoline ribonucleoside, Neq135, is the first low micromolar trypanosomatidae inhibitor to show good ligand efficiency (0.28 kcal mol-1 atom-1) and good ligand lipophilicity efficiency (0.37 kcal mol-1/sup
- Soares, Fabyana A.,Sesti-Costa, Renata,Da Silva, Jo?o Santana,De Souza, Maria Cecília B.V.,Ferreira, Vitor F.,Da C. Santos, Fernanda,Monteiro, Patricia A.U.,Leit?o, Andrei,Montanari, Carlos A.
-
supporting information
p. 4597 - 4601
(2013/08/15)
-
- Oxoquinoline acyclonucleoside phosphonate analogues as a new class of specific inhibitors of human immunodeficiency virus type 1
-
The emergence of a multidrug-resistant HIV-1 strain and the toxicity of anti-HIV-1 compounds approved for clinical use are the most significant problems facing antiretroviral therapies. Therefore, it is crucial to find new agents to overcome these issues. In this study, we synthesized a series of new oxoquinoline acyclonucleoside phosphonate analogues (ethyl 1- [(diisopropoxyphosphoryl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylates 3a-3k), which contained different substituents at the C6 or C7 positions of the oxoquinoline nucleus and an N1-bonded phosphonate group. We subsequently investigated these compounds' in vitro inhibitory effects against HIV-1-infected peripheral blood mononuclear cells (PBMCs). The most active compounds were the fluoro-substituted derivatives 3f and 3g, which presented excellent EC 50 values of 0.4 ± 0.2 μM (3f) and 0.2 ± 0.005 μM (3g) and selectivity index values (SI) of 6240 and 14675, respectively.
- Faro, Leticia V.,De Almeida, Jessica M.,Cirne-Santos, Claudio C.,Giongo, Viveca A.,Castello-Branco, Luis R.,Oliveira, Ingrid De B.,Barbosa, Juliana E.F.,Cunha, Anna C.,Ferreira, Vitor F.,De Souza, Marcos C.,Paixao, Izabel C.N.P.,De Souza, Maria Cecilia B.V.
-
scheme or table
p. 5055 - 5058
(2012/08/28)
-
- Synthesis and anticancer activities of some novel 2-(benzo[d]thiazol-2-yl)- 8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones
-
A series of 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c] quinolin-3(5H)-ones (3a-g) have been synthesized and evaluated for their in vitro antiproliferative activities against four human cancer cell lines: MDA-MB-435 (breast), HL-60 (leukemia), HCT-8 (colon) and SF-295 (central nervous system). The results showed that the compounds 3b (2-(benzo[d]thiazol-2-yl)-8- methyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) and 3c (2-(benzo[d]thiazol-2-yl)-8- bromo-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) exhibited good cytotoxicity for three cell lines with IC50 values lower than 5 μg/mL. Analysis of theoretical toxicity risks have shown medium tumorigenic and irritant risks related to 3b and 3c in contrast to doxorubicin, the positive control.
- Reis, Raísa Da R.,Azevedo, Elisa C.,De Souza, Maria Cecília B.V.,Ferreira, Vitor Francisco,Montenegro, Raquel C.,Araújo, Ana Jérsia,Pessoa, Cláudia,Costa-Lotufo, Letícia V.,De Moraes, Manoel O.,Filho, José D.B.M.,De Souza, Alessandra M.T.,De Carvalho, Natasha C.,Castro, Helena C.,Rodrigues, Carlos R.,Vasconcelos, Thatyana R.A.
-
experimental part
p. 1448 - 1452
(2011/04/24)
-
- Synthesis and Na+/H+ exchanger-1 inhibitory activity of substituted (quinolinecarbonyl)guanidine derivatives
-
The Na+/H+ exchanger (NHE) is a protein expressed in many mammalian cell types. It is involved in intracellular pH (pHi) homeostasis by exchanging extracellular Na+ for intracellular H +. To date, nine NHE isoforms (NHE1-NHE9) have been identified. NHE1 is the most predominant isoform expressed in mammalian cardiac muscle. A novel series of substituted (quinolinecarbonyl)guanidine derivatives were designed and synthesized as NHE inhibitors. Most compounds can inhibit NHE1-mediated platelet swelling in a concentration-dependent manner, among which compound 7f was the most active and more potent than cariporide. Furthermore, compound 7f has also been demonstrated to exhibit the in vivo cardioprotective effects against SD rat myocardial ischemic-reperfusion injury superior to those of cariporide.
- Mao, Dan,Xu, Yungen,Hu, Xiaoping,Zhang, Guomin,Dong, Jin,Gong, Guoqing
-
experimental part
p. 1727 - 1736
(2010/05/18)
-
- Design, synthesis, and biological evaluation of novel quinoline derivatives as HIV-1 Tat-TAR interaction inhibitors
-
Thirty-two quinoline derivatives were designed and synthesized as HIV-1 Tat-TAR interaction inhibitors. All the compounds showed high antiviral activities in inhibiting the formation of SIV-induced syncytium in CEM174 cells. Nine of them with low cytotoxicities were evaluated by Tat dependent HIV-1 LTR-driven CAT gene expression colorimetric enzyme assay in human 293T cells, indicating effective inhibitory activities of blocking the Tat-TAR interaction. Molecular modeling experiments indicated that these compounds may inhibit Tat-TAR interaction by binding to Tat protein instead of TAR RNA.
- Chen, Shuguang,Chen, Ran,He, Meizi,Pang, Ruifang,Tan, Zhiwu,Yang, Ming
-
experimental part
p. 1948 - 1956
(2009/05/26)
-
- Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase
-
Pyrimidine biosynthesis presents an attractive drug target in malaria parasites due to the absence of a pyrimidine salvage pathway. A set of compounds designed to inhibit the Plasmodium falciparum pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (PfDHODH) was synthesized. PfDHODH-specific inhibitors with low nanomolar binding affinities were identified that bind in the N-terminal hydrophobic channel of dihydroorotate dehydrogenase, the presumed site of ubiquinone binding during oxidation of dihydroorotate to orotate. These compounds also prevented growth of cultured parasites at low micromolar concentrations. Models that suggest the mode of inhibitor binding is based on shape complementarity, matching hydrophobic regions of inhibitor and enzyme, and interaction of inhibitors with amino acid residues F188, H185, and R265 are supported by mutagenesis data. These results further highlight PfDHODH as a promising new target for chemotherapeutic intervention in prevention of malaria and provide better understanding of the factors that determine specificity over human dihydroorotate dehydrogenase.
- Heikkil?, Timo,Ramsey, Christopher,Davies, Matthew,Galtier, Christophe,Stead, Andrew M. W.,Johnson, A. Peter,Fishwick, Colin W. G.,Boa, Andrew N.,McConkey, Glenn A.
-
p. 186 - 191
(2007/10/03)
-
- Evaluation of 3-carboxy-4(1H)-quinolones as inhibitors of human protein kinase CK2
-
Due to the emerging role of protein kinase CK2 as a molecule that participates not only in the development of some cancers but also in viral infections and inflammatory failures, small organic inhibitors of CK2, besides application in scientific research, may have therapeutic significance. In this paper, we present a new class of CK2 inhibitors-3-carboxy-4(1H)-quinolones. This class of inhibitors has been selected via receptor-based virtual screening of the Otava compound library. It was revealed that the most active compounds, 5,6,8-trichloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7) (IC 50 = 0.3 μM) and 4-oxo-1,4-dihydrobenzo[h]quinoline-3-carboxylic acid (9) (IC50 = 1 μM), are ATP competitive (Ki values are 0.06 and 0.28 μM, respectively). Evaluation of the inhibitors on seven protein kinases shows considerable selectivity toward CK2. According to theoretical calculations and experimental data, a structural model describing the key features of 3-carboxy-4(1H)-quinolones responsible for tight binding to CK2 active site has been developed.
- Golub, Andriy G.,Yakovenko, Olexander Ya.,Bdzhola, Volodymyr G.,Sapelkin, Vladislav M.,Zien, Piotr,Yarmoluk, Sergiy M.
-
p. 6443 - 6450
(2007/10/03)
-
- Synthesis and anti-HSV-1 activity of quinolonic acyclovir analogues
-
Several 1-[(2-hydroxy-ethoxy)methyl]-3-carbethoxy-4(1H)quinolones (2a-l) and l-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxylic acids (3a-j and 3l) were synthesized and 2a-j, 2l and 3a-j, 3l were evaluated against herpes simplex virus type 1 (HSV-1), employing a one-pot reaction: silylation of the desired quinolone (BSTFA 1% TMCS) followed by equimolar amount addition of 1,3-dioxolane, chlorotrimethylsilane and KI, at room temperature. The acyclonucleosides 2a-l were obtained in 40-77% yields. The esters 2a-j and 2l were subsequently converted into the corresponding hydroxyacids 3 in 40-70% yields. Attempts of hydrolysis of 2k produced only a mixture of degradation products. Antiviral activity of 2 and 3 on HSV-1 virus infection was assessed by the virus yield assay. Except for compounds 2i and 3e, the acyclonucleosides were found to reduce the virus yield by 70-99% at the concentration of 50 μM, being the acids, in general, more effective inhibitors than their corresponding esters. Compounds 3j and 2d exhibited antiviral activity against HSV-1 virus with EC50 of 0.7 ± 0.04 and 0.8 ± 0.09 μM, respectively. Both compounds were not toxic towards the Vero cell line.
- Lucero, Bianca D'A.,Gomes, Claudia Regina B.,Frugulhetti, Izabel Christina De P.P.,Faro, Leticia V.,Alvarenga, Lise,De Souza, Maria Cecilia B.V.,De Souza, Thiago M.L.,Ferreira, Vitor F.
-
p. 1010 - 1013
(2008/12/23)
-
- Design, synthesis, and biological evaluation of novel 4-hydro-quinoline-3- carboxamide derivatives as an immunomodulator
-
A series of novel quinoline-3-carboxamide derivatives were synthesized and evaluated for their immunomodulatory activity. The compounds were tested in vitro for effects on spleen lymphocyte proliferation and TNF-α production by macrophage. Three compounds showed immunomodulatory profiles similar to and more potent than those of linomide and FR137316 and were selected for further pharmacological studies in vivo.
- He, Jun-Feng,Yun, Liu-Hong,Yang, Ri-Fang,Xiao, Zhi-Yong,Cheng, Jun-Ping,Zhou, Wen-Xia,Zhang, Yong-Xiang
-
p. 2980 - 2985
(2007/10/03)
-
- Microwave assisted Gould-Jacob reaction: Synthesis of 4-quinolones under solvent free conditions
-
A single step Gould-Jacob reaction between aromatic amines and diethyl ethoxymethylenemalonates (EMME) for the synthesis of 4-quinolones under solvent free microwave irradiation has been carried out and compared with classical heating.
- Dave, Chaitanya G.,Joshipura, Hardik M.
-
p. 650 - 652
(2007/10/03)
-
- Structure-activity relationship investigations of the modulating effect of core substituents on the affinity of pyrazoloquinolinone congeners for the benzodiazepine receptor
-
A series of 6- and 7-substituted-2-arylpyrazolo [4,3-c] quinolin-3-ones was synthesized and tested in vitro for binding with the benzodiazepine receptor in competition with [3H]flunitrazepam. Electronic parameters (molecular electrostatic potential (MEP), charge distribution on the nitrogen atoms, dipole moment μ, and ionization potential (IP) were calculated for the compounds by semi-empirical quantum chemistry methods. Lipophilicity of the compounds, expressed as logarithm of the octanol-water partition coefficient (log P), was calculated by the program Pallas. A quantitative correlation of the biological data with molecular parameters revealed a significant dependence (r = 0.95) of the activity on hydrophobic constants of the substituents, log P, and magnitude of the MEP minimum associated with the carbonyl oxygen atom.
- Karolak-Wojciechowska, Janina,Lange, Jerzy,Ksiazek, Waldemar,Gniewosz, Malgorzata,Rump, Slawomir
-
p. 579 - 585
(2007/10/03)
-
- Nucleosides having quinolone derivatives as nitrogenated base : Regiospecific and stereospecific rdsosylation of 3-carbethoxy-1,4-dihydro-4-oxoquinolines
-
Ribosylation reactions of previously silylated 3-carbethoxy-8-methyl-1,4-dihydro-4-oxoquinoline (6a) and 3-carbethoxy-6-methyl-1,4-dihydro-4-oxoquinoline (6b) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (7), under Lewis acid catalysis, were studi
- Da Matta,Bernardino,Romeiro,De Oliveira,De Souza,Ferreira
-
p. 889 - 898
(2007/10/03)
-
- PREPARATION OF PROPANEDIOIC ACID, (ANILINOMETHYLENE) ALKYL ESTERS BY DIRECT CONDENSATION
-
The title compounds, 7a-e, were obtained by direct acid catalyzed condensation of diethyl malonate and triethyl ortho formate, with the corresponding aniline in acetic anhydride.In the absence of acetic anhydride amido esters 8a-e were formed.
- Munoz, Heber,Tamariz, Joaquin,Zamora, Hector Salgado,Lazaro, Miguel,Labarrios, Fernando
-
p. 549 - 554
(2007/10/02)
-
- Vibrational Spectroscopy and Conformations of 2-Alkoxycarbonyl-3-aminoacrylic Esters
-
The i.r., Raman, and 1H n.m.r. spectra of 2-alkoxycarbonyl-3-aminoacrylic esters (IV; R1=H, alkyl, aryl) and those of their N-deuteriated derivatives show that these substances exist in the enamino-ester form with a strong intramolecular hydrogen bond between the cis-NH (or -ND) and CO2R2 groups.Some complexities in the i.r. and Raman bands, and their dependence on solvent polarity, temperature, and aggregation state, indicate the existence of rotational isomerism: conformers (IVa and b) predominate in non-polar media; an additional rotamer (IVd) is also probably present in polar solvents.Conformation (IVb) is preferred in the solid state.Some features of the ν(C=O) bands suggest a weak vibrational coupling between the carbonyls.The validity of the criteria established by Smith and Taylor to ascertain the planarity of these and related substances is discussed, and no significant difference in this respect is considered to exist between compounds (IV) with primary and secondary amino-groups.
- Gomez-Sanchez, Antonio,Sempere, Eugenia,Bellanato, Juana
-
p. 561 - 570
(2007/10/02)
-