132-60-5Relevant articles and documents
5-HT3 Receptor Antagonists. 3. Quinoline Derivatives Which May Be Effective in the Therapy of Irritable Bowel Syndrome
Kishibayashi, Nobuyuki,Miwa, Yoshikazu,Hayashi, Hiroaki,Ishii, Akio,Ichikawa, Shunji,et al.
, p. 3286 - 3292 (1993)
A series of quinolinecarboxylic acid derivatives has been previously described as a new class of 5-HT3 receptor antagonists due to deviation of a carbonyl moiety from the plane of an aromatic ring in their minimum-energy conformations.These derivatives were evaluated in a wrap-restraint stress-induced defecation model in rats.Reference compounds, ondansetron (1), granisetron (2), and YM060 (4), potently inhibited a stress-induced increase in stools excreted from fed rats (ID50 = 0.27, 0.12, and 0.0052 mg/kg, po, respectively).However, quinoline derivatives exhibited different activities depending on structural class. 4-Hydroxyquinoline-3-carboxylic acid derivatives 5 and 6a possess high affinity for the 5-HT3 receptor (Ki = 6.1 and 1.5 nM, respectively) and exhibit potent activity in the Bezold-Jarisch (B-J) reflex test (ED50 = 0.0017 and 0.00010 mg/kg, iv, respectively), but they did not effectively inhibit the increase in fecal pellet output at the dose of 1 mg/kg, po.On the other hand, most of 1-substituted 2-oxoquinoline-4-carboxylates 10 showed less potent activity in the B-J reflex test than 1 or 2 but inhibited restraint stress-induced defecation more potently than 1 or 2.The ID50 value of endo-8-methyl-8-azabicyclooct-3-yl 1-isobutyl-2-oxo-1,2-dihydro-4-quinolinecarboxylate 10e was 0.013 mg/kg, po.With respect to the selected compounds 6a and 10e, effects on 5-HT- and thyrotropin-releasing hormone (TRH)-induced defecation, castor oil-induced diarrhea and wrap-restraint stress-induced colonic propulsion in rats were examined.These 5-HT3 receptor antagonists did not effectively inhibit castor oil-induced diarrhea, which has been reported not to be mediated via the 5-HT3 receptor.Although 10e showed 800-fold decreased potency compared with 4 in the B-J refles test, 10e exhibited activity as potent as 4 in 5-HT- and TRH-induced defecation assays; 10e exhibited 7-fold increased potency compared with 4 in wrap-restraint stress-induced colonic propulsions.From these results, 10e appears to interact selectively with 5-HT3 receptors in the gastrointestinal system and might be effective in the therapy of irritable bowel syndrome (IBS).
Design and synthesis of novel quinoline/chalcone/1,2,4-triazole hybrids as potent antiproliferative agent targeting EGFR and BRAFV600E kinases
Mohassab, Aliaa M.,Hassan, Heba A.,Abdelhamid, Dalia,Gouda, Ahmed M.,Youssif, Bahaa G.M.,Tateishi, Hiroshi,Fujita, Mikako,Otsuka, Masami,Abdel-Aziz, Mohamed
, (2021)
New quinoline / chalcone hybrids containing 1,2,4-triazole moiety have been designed, synthesized and their structures elucidated and confirmed by various spectroscopic techniques. The designed compounds showed moderate to good activity on different NCI 60 cell lines in a single-dose assay with a growth inhibition rate ranging from 50% to 94%. Compounds 7b, 7d, 9b, and 9d were the most active compounds in most cancer cell lines with a growth inhibition percent between 77% and 94%. Newly synthesized hybrids were evaluated for their anti-proliferative activity against a panel of four human cancer cell lines. Compounds 7a, 7b, 9a, 9b, and 9d showed promising antiproliferative activities. These compounds were further tested for their inhibitory potency against EGFR and BRAFV600E kinases with erlotinib as a reference drug. The molecular docking study of compounds 7a, 7b, 9a, 9b, and 9d revealed nice fitting into the active site of EGFR and BRAFV600E kinases. Compounds 7b, 9b, and 9d displayed the highest binding affinities and similar binding pattern to those of erlotinib.
NO-releasing STAT3 inhibitors suppress BRAF-mutant melanoma growth
Kaoud, Tamer S.,Mohassab, Aliaa M.,Hassan, Heba A.,Yan, Chunli,Van Ravenstein, Sabrina X.,Abdelhamid, Dalia,Dalby, Kevin N.,Abdel-Aziz, Mohamed
, (2020)
Constitutive activation of STAT3 can play a vital role in the development of melanoma. STAT3-targeted therapeutics are reported to show efficacy in melanomas harboring the BRAFV600E mutant and also in vemurafenib-resistant melanomas. We designed and synthesized a series of substituted nitric oxide (NO)-releasing quinolone-1,2,4-triazole/oxime hybrids, hypothesizing that the introduction of a STAT3 binding scaffold would augment their cytotoxicity. All the hybrids tested showed a comparable level of in vitro NO production. 7b and 7c exhibited direct binding to the STAT3-SH domain with IC50 of ～ 0.5 μM. Also, they abrogated STAT3 tyrosine phosphorylation in several cancer cell lines, including the A375 melanoma cell line that carries the BRAFV600E mutation. At the same time, they did not affect the phosphorylation of upstream kinases or other STAT isoforms. 7c inhibited STAT3 nuclear translocation in mouse embryonic fibroblast while 7b and 7c inhibited STAT3 DNA-binding activity in the A375 cell line. Their anti-proliferating activity is attributed to their ability to trigger the production of reactive oxygen species and induce G1 cell cycle arrest in the A375 cell line. Interestingly, 7b and 7c showed robust cell growth suppression and apoptosis induction in two pairs of BRAF inhibitor-na?ve (-S) and resistant (-R) melanoma cell lines containing a BRAF V600E mutation. Surprisingly, MEL1617-R cells that are known to be more resistance to MEK inhibition by GSK1120212 than MEL1617-S cells exhibit a similar response to 7b and 7c.
Design and Synthesis of 2,5-Disubstituted-1,3,4-Oxadiazole Hybrids Bearing Pyridine and 1,2,3-Triazole Pharmacophores
Kaushik, Reena,Kushwaha, Khushbu,Chand, Mahesh,Vashist, Monika,Jain, Subhash C.
, p. 1042 - 1047 (2017)
A novel series of 2,5-disubstituted-1,3,4-oxadiazoles decorated with two biodynamic moieties pyridine and 1,2,3-triazole have been successfully synthesized in good yields under mild reaction conditions. The synthesized compounds are valuable for biological activity exploration since three biodynamic moieties are covalently linked together in a single molecular framework. All the synthesized compounds were fully characterized by their detailed spectral studies IR, 1HNMR, 13C NMR and Mass.
PRODUCTION METHOD OF QUINOLINECARBOXAMIDE DERIVATIVE OR PRODUCTION INTERMEDIATE THEREOF
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, (2022/06/03)
Provided is a method for industrially advantageously synthesizing a production intermediate of a quinolinecarboxamide derivative or a salt thereof. The present invention provides a method for producing a quinolinecarboxylic acid derivative of formula (4) or a salt thereof, including reacting an aniline of the following formula (1), in the presence of boron trifluoride-tetrahydrofuran complex or boron trifluoride-diethyl ether complex, with an aldehyde of formula (2) and subsequently reacting the resulting compound with an α-keto acid of formula (3), wherein R1, R2, R3 and R4 are the same or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group, or the like, R5 represents a hydrogen atom, a lower alkyl group, or the like, and R6 represents a hydrogen atom, a lower alkyl group, or the like.
Design, synthesis, and antibacterial evaluation of new quinoline-1,3,4-oxadiazole and quinoline-1,2,4-triazole hybrids as potential inhibitors of DNA gyrase and topoisomerase IV
Hofny, Heba A.,Mohamed, Mamdouh F.A.,Gomaa, Hesham A.M.,Abdel-Aziz, Salah A.,Youssif, Bahaa G.M.,El-koussi, Nawal A.,Aboraia, Ahmed S.
, (2021/04/29)
DNA gyrase and topoisomerase IV (topo IV) inhibitors are among the most interesting antibacterial drug classes without antibacterial pipeline representative. Twenty-four new quinoline-1,3,4-oxadiazole and quinoline-1,2,4-triazole hybrids were developed and tested against DNA gyrase and topoisomerase IV from Escherichia coli and Staphylococcus aureus. The most potent compounds 4c, 4e, 4f, and 5e displayed an IC50 of 34, 26, 32, and 90 nM against E. coli DNA gyrase, respectively (novobiocin, IC50 = 170 nM). The activities of 4c, 4e, 4f, and 5e on DNA gyrase from S. aureus were weaker than those on E. coli gyrase. Compound 4e showed IC50 values (0.47 μM and 0.92 μM) against E. coli topo IV and S. aureus topo IV, respectively in comparison to novobiocin (IC50 = 11, 27 μM, respectively). Antibacterial activity against Gram-positive and Gram-negative bacterial strains has been studied. Some compounds have demonstrated superior antibacterial activity to ciprofloxacin against some of the bacterial strain studied. The most active compounds in this study showed no cytotoxic effect with cell viability>86%. Finally, a molecular docking analysis was performed to investigate the binding mode and interactions of the most active compounds to the active site of DNA gyrase and topoisomerase IV (topo IV) enzymes.
Quinoline carboxamide core moiety-based compounds inhibit P. falciparum falcipain-2: Design, synthesis and antimalarial efficacy studies
Singh, Anju,Kalamuddin, Md,Maqbool, Mudasir,Mohmmed, Asif,Malhotra, Pawan,Hoda, Nasimul
, (2020/12/07)
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.
Synthesis of Novel Quinoline–Benzoxazolinone Ester Hybrids: In Vitro Anti-Inflammatory Activity and Antibacterial Activity
Shaikh, Sarfaraz F.,Dhavan, Pratik P.,Singh, Pinky R.,Vaidya,Jadhav,Ramana
, p. 572 - 583 (2021/05/03)
Abstract: A series of novel quinoline-benzoxazolinone ester hybrids were synthesized characterized and assessed for their in vitro anti-inflammatory and antibacterial activity. The in vitro anti-inflammatory activity was executed using protein denaturation assay, proteinase inhibitory assay and human red blood cell membrane stabilization assay. Most of the compounds exhibited potential anti-inflammatory activity. Compound (2-oxobenzo[d]oxazol-3(2H)-yl)methyl-2-(thiophen-2-yl)quinoline-4-carboxylate showed a better anti-inflammatory activity than the standard drugs diclofenac sodium and indomethacin. Furthermore, antibacterial activities of the synthesized compounds were evaluated using resazurin microtiter assay (REMA) and were compared with a positive drug standard chloramphenicol. The compounds demonstrated moderate to potent antibacterial activity. (2-Oxobenzo[d]oxazol-3(2H)-yl)methyl-2-(3,4-dimethoxyphenyl)quinoline-4-carboxylate and (2-oxobenzo[d]oxazol-3(2H)-yl)methyl-2-(2-chlorophenyl)quinoline-4-carboxylate displayed excellent activity against all bacterial strains in comparison to standard chloramphenicol. Moreover, cytotoxicity was performed on MDCK cells using MTT assay and it was found that none of the synthesized derivatives possessed any cytotoxicity.
New quinoline/1,2,4-triazole hybrids as dual inhibitors of COX-2/5-LOX and inflammatory cytokines: Design, synthesis, and docking study
Abdel-Aziz, Mohamed,Abdelhamid, Dalia,Fujita, Mikako,Gomaa, Hesham A. M.,Gouda, Ahmed M.,Hassan, Heba A.,Mohassab, Aliaa M.,Otsuka, Masami,Radwan, Mohamed O.,Youssif, Bahaa G. M.
, (2021/07/06)
A novel series of 19 quinoline/1,2,4-triazole hybrid 6a-i and 7a-j was synthesized and evaluated in vitro as dual COX-2/5-LOX inhibitors. Compounds 6e, 6i, and 7e displayed the highest potency and selectivity for inhibiting COX-2 activity (IC50 = 7.25, 8.13, and 8.48 nM, respectively; selectivity index (COX-1/COX-2) = 44.89, 30.30, and 33.47, respectively) in comparison to celecoxib (COX-2 IC50 = 42.60 nM; selectivity index (SI) = 8.05). The anti-inflammatory activity of the newly synthesized compounds was further examined in vivo using a carrageenan induced paw edema assay. Interestingly, the in vitro findings of the COX inhibitory assay were consistent with the in vivo assay. Moreover, 6e, 6i, and 7e showed a substantial reduction in serum concentrations of PGE2, TNF-α, IL-6. Molecular docking analysis of compounds 6e, 6f, 6i, 7e, and 7f revealed high binding affinities toward COX-2 compared to COX-1, which was matched with the experimental results. In addition, these compounds exhibited different binding orientations into the active site of COX-2, which were dependent on the type of substitutions on N4 of the triazole ring. Among the tested derivatives, compounds 6e, 6i and 7e which showed high selectivity to COX-2, exhibited hydrogen bonding interactions with key amino acids in COX-2 such as Arg120, Arg513, and/or Glu524. In addition, the tested compounds also showed multiple hydrogen bonds with the Arg101, Val110, Arg138 or His130 in 5-LOX. These findings show, taken together, that those derivatives are good leads to potential anti-inflammatory agents with lowest gastric damage.
Synthesis, Antibacterial, Antioxidant, and Molecular Modeling Studies of Novel [2,3′-Biquinoline]-4-Carboxylic Acid and Quinoline-3-Carbaldehyde Analogs
Digafie, Zeleke,Melaku, Yadessa,Belay, Zerihun,Eswaramoorthy, Rajalakshmanan
, (2021/05/19)
Currently, it has been common to see people being affected and dying from untreatable infections caused by multidrug-resistant (MDR) germs. To tackle this problem, developing new effective chemotropic agents is urgently needed. Hence, this project aims to design, synthesize, and evaluate their antibacterial and antioxidant activities of new series of [2,3′-biquinoline]-4-carboxylic acid and quinoline-3-carbaldehyde analogs. The molecular docking analysis of the compounds against E. coli DNA gyrase was computed to investigate the binding mode of the compounds within the active site of the enzyme. In this regard, a new series of [2,3′-biquinoline]-4-carboxylic acid and quinoline-3-carbaldehyde analogs were synthesized by utilization of Vilsmeier-Haack, Doebner, nucleophilic substitution, and hydrolysis reactions. The structures of the synthesized compounds were determined using UV-Vis, FT-IR, and NMR. The synthesized compounds were screened for their antibacterial activity against four bacterial strains using disc diffusion methods. The findings of the study revealed that seven of synthetic compounds possess good antibacterial activity compared to ciprofloxacin which was used as a positive control in the experiment. Among them, compounds 4, 9, and 10 displayed the highest mean inhibition zone of 13.7 ± 0.58, 16.0 ± 1.7, and 20.7 ± 1.5 mm, respectively, at 0.1 μg/μL. The radical scavenging property of these compounds was evaluated using DPPH radical assay where compounds 9 and 20 showed the strongest activity with IC50 values of 1.25 and 1.75 μg/mL, respectively. At the same concentration, the IC50 value of ascorbic acid was 4.5 μg/mL. The synthesized compounds were also assessed for their in silico molecular docking analysis. Compounds 4 (-6.9 kcal/mol), 9 (-6.9 kcal/mol), and 10 (-7.9 kcal/mol) showed the maximum binding affinity close to ciprofloxacin (-7.2 kcal/mol) used as a positive control. Thus, compounds 4, 9, and 10 showed the best antibacterial activities in both in vitro and molecular docking analyses among the synthetic compounds. The results of in silico molecular docking evaluation of the synthetic compounds against E. coli DNA gyrase B were in good agreement with the in vitro antibacterial analysis. Therefore, the antibacterial activity displayed by these compounds is encouraging for further investigation to improve the activities of [2,3′-biquinoline]-4-carboxylic acid by incorporating various bioisosteric groups in either of the quinoline rings.
