16803-92-2Relevant articles and documents
Comparative study between the anti-P. falciparum activity of triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives and the identification of new PfDHODH inhibitors
Silveira, Flávia F.,de Souza, Juliana O.,Hoelz, Lucas V.B.,Campos, Vinícius R.,Jabor, Valquíria A.P.,Aguiar, Anna C.C.,Nonato, M. Cristina,Albuquerque, Magaly G.,Guido, Rafael V.C.,Boechat, Nubia,Pinheiro, Luiz C.S.
, (2020/11/10)
In this work, we designed and synthesized 35 new triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives as P. falciparum inhibitors (3D7 strain). Thirty compounds exhibited anti-P. falciparum activity, with IC50 values ranging from 0.030 to 9.1 μM. The [1,2,4]triazolo[1,5-a]pyrimidine derivatives were more potent than the pyrazolo[1,5-a]pyrimidine and quinoline analogues. Compounds 20, 21, 23 and 24 were the most potent inhibitors, with IC50 values in the range of 0.030–0.086 μM and were equipotent to chloroquine. In addition, the compounds were selective, showing no cytotoxic activity against the human hepatoma cell line HepG2. All [1,2,4]triazolo[1,5-a]pyrimidine derivatives inhibited PfDHODH activity in the low micromolar to low nanomolar range (IC50 values of 0.08–1.3 μM) and did not show significant inhibition against the HsDHODH homologue (0–30% at 50 μM). Molecular docking studies indicated the binding mode of [1,2,4]triazolo[1,5-a]pyrimidine derivatives to PfDHODH, and the highest interaction affinities for the PfDHODH enzyme were in agreement with the in vitro experimental evaluation. Thus, the most active compounds against P. falciparum parasites 20 (R = CF3, R1 = F; IC50 = 0.086 μM), 21 (R = CF3; R1 = CH3; IC50 = 0.032 μM), 23, (R = CF3, R1 = CF3; IC50 = 0.030 μM) and 24 (R = CF3, 2-naphthyl; IC50 = 0.050 μM) and the most active inhibitor against PfDHODH 19 (R = CF3, R1 = Cl; IC50 = 0.08 μM - PfDHODH) stood out as new lead compounds for antimalarial drug discovery. Their potent in vitro activity against P. falciparum and the selective inhibition of the PfDHODH enzyme strongly suggest that this is the mechanism of action underlying this series of new [1,2,4]triazolo[1,5-a]pyrimidine derivatives.
Structure-activity relationships of agonists for the orphan G protein-coupled receptor GPR27
Blavier, Jeremy,Charles, Ma?lle,Hanson, Julien,Kronenberger, Thales,Laschet, Céline,Müller, Christa E.,Pillaiyar, Thanigaimalai,Rosato, Francesca,Wozniak, Monika
, (2021/08/27)
GPR27 belongs, with GPR85 and GPR173, to a small subfamily of three receptors called “Super-Conserved Receptors Expressed in the Brain” (SREB). It has been postulated to participate in key physiological processes such as neuronal plasticity, energy metabolism, and pancreatic β-cell insulin secretion and regulation. Recently, we reported the first selective GPR27 agonist, 2,4-dichloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (I, pEC50 6.34, Emax 100%). Here, we describe the synthesis and structure-activity relationships of a series of new derivatives and analogs of I. All products were evaluated for their ability to activate GPR27 in an arrestin recruitment assay. As a result, agonists were identified with a broad range of efficacies including partial and full agonists, showing higher efficacies than the lead compound I. The most potent agonist was 4-chloro-2,5-difluoro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7y, pEC50 6.85, Emax 37%), and the agonists with higher efficacies were 4-chloro-2-methyl-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7p, pEC50 6.04, Emax 123%), and 2-bromo-4-chloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7r, pEC50 5.99, Emax 123%). Docking studies predicted the putative binding site and interactions of agonist 7p with GPR27. Selected potent agonists were found to be soluble and devoid of cellular toxicity within the range of their pharmacological activity. Therefore, they represent important new tools to further characterize the (patho)physiological roles of GPR27.
Synthesis, characterization, crystal structures and biological screening of 4-amino quinazoline sulfonamide derivatives
Sunil Kumar,Kudva, Jyothi,Lahtinen, Manu,Peuronen, Anssi,Sadashiva, Rajitha,Naral, Damodara
, p. 29 - 36 (2019/05/01)
Three quinazolin-4-ylamino derivatives containing phenylbenzenesulfonamides (7a-7c)were synthesized by reacting (E)-N'-(2-cyanophenyl)-N,N-dimethyl formamidine (6)with different 4-amino-N-(phenyl)benzenesulfonamides (4a-4c)and characterized by different techniques such as HRMS, IR, 1H NMR and 13C NMR spectroscopy. The structural properties were further examined by single crystal X-ray diffraction method. The X-ray data shows that compounds 7a and 7c contain two molecules and 7b contains one molecule in the asymmetric unit. Comparison of conformation of two distinct molecules, “A” and “B”, in the asymmetric unit of 7a and 7c were studied with the aid of reported literature. The in vitro antiproliferative activity of the compounds was tested against two breast cancer cell lines (MDA-MB-231 and MCF7). Compound 7b observed as a highest potent candidate against MDA-MB-231with IC50 of 5.44 μg/mL. Antimicrobial activity was also screened against bacterial and fungal strains. Compound 7a with chloro substitution was observed as the most potent candidate against the Gram-negative bacterial strains, whereas the compounds showed no significant activity against the fungal strain.
Synthesis, structural, biological and in silico studies of new 5-arylidene-4-thiazolidinone derivatives as possible anticancer, antimicrobial and antitubercular agents
Sunil Kumar,Kudva, Jyothi,Bharath,Ananda,Sadashiva, Rajitha,Madan Kumar,Revanasiddappa,Kumar, Vasantha,Rekha,Naral, Damodara
, p. 1597 - 1610 (2019/01/21)
A new series of halogenated 4-thiazolidinone derivatives bearing the sulfonamide moiety was synthesized and characterized via FT-IR, 1H NMR, 13C NMR, HRMS and single crystal X-ray analysis. The newly synthesized target compounds were screened for their in vitro cytotoxicity on the HepG2 and MDA-MB-231 cell lines, and antimicrobial and antitubercular activity. The compounds showed promising anticancer activity towards the MDA-MB-231 cell line, and the trichloro derivatives with p-chloro substitution (6i) and p-hydroxy substitution (7e) exhibited excellent anticancer activity. Compounds 6b and 7c were observed to be moderate antimicrobial agents. The seven most potent anticancer agents were further studied for their antitubercular activity against an M. tuberculosis strain and it was found that compound 7e showed significant antitubercular activity. The potent candidates were also tested for hemolysis activity against human RBC cells and were found to be non-toxic. The mode of action for the observed anticancer activity was further supported by molecular docking studies of the potent compounds against the enzyme Aurora kinase (PDB ID: 4ZTR). Molecular dynamics (MD) simulations were further performed to study the stability of the ligand-protein complex.
Synthesis, molecular structure, anticancer activity, and QSAR study of N-(Aryl/heteroaryl)-4-(1h-pyrrol-1-yl)benzenesulfonamide derivatives
?o?nowska, Beata,S?awiński, Jaros?aw,Brzozowski, Zdzis?aw,Kawiak, Anna,Belka, Mariusz,Zielińska, Joanna,Baczek?, Tomasz,Chojnacki, Jaros?aw
, (2018/05/25)
A series of N-(aryl/heteroaryl)-4-(1H-pyrrol-1-yl)benzenesulfonamides were synthesized from 4-amino-N-(aryl/heteroaryl)benzenesulfonamides and 2,5-dimethoxytetrahydrofuran. All the synthesized compounds were evaluated for their anticancer activity on HeLa, HCT-116, and MCF-7 human tumor cell lines. Compound 28, bearing 8-quinolinyl moiety, exhibited the most potent anticancer activity against the HCT-116, MCF-7, and HeLa cell lines, with IC50 values of 3, 5, and 7 μM, respectively. The apoptotic potential of the most active compound (28) was analyzed through various assays: phosphatidylserine translocation, cell cycle distribution, and caspase activation. Compound 28 promoted cell cycle arrest in G2/M phase in cancer cells, induced caspase activity, and increased the population of apoptotic cells. Relationships between structure and biological activity were determined by the QSAR (quantitative structure activity relationships) method. Analysis of quantitative structure activity relationships allowed us to generate OPLS (Orthogonal Projections to Latent Structure) models with verified predictive ability that point out key molecular descriptors influencing benzenosulfonamide’s activity.
Design, synthesis, and evaluation of substituted nicotinamide adenine dinucleotide (NAD+) synthetase inhibitors as potential antitubercular agents
Wang, Xu,Ahn, Yong-Mo,Lentscher, Adam G.,Lister, Julia S.,Brothers, Robert C.,Kneen, Malea M.,Gerratana, Barbara,Boshoff, Helena I.,Dowd, Cynthia S.
supporting information, p. 4426 - 4430 (2017/09/12)
Nicotinamide adenine dinucleotide (NAD+) synthetase catalyzes the last step in NAD+ biosynthesis. Depletion of NAD+ is bactericidal for both active and dormant Mycobacterium tuberculosis (Mtb). By inhibiting NAD+ synthetase (NadE) from Mtb, we expect to eliminate NAD+ production which will result in cell death in both growing and nonreplicating Mtb. NadE inhibitors have been investigated against various pathogens, but few have been tested against Mtb. Here, we report on the expansion of a series of urea-sulfonamides, previously reported by Brouillette et al. Guided by docking studies, substituents on a terminal phenyl ring were varied to understand the structure–activity-relationships of substituents on this position. Compounds were tested as inhibitors of both recombinant Mtb NadE and Mtb whole cells. While the parent compound displayed very weak inhibition against Mtb NadE (IC50 = 1000 μM), we observed up to a 10-fold enhancement in potency after optimization. Replacement of the 3,4-dichloro group on the phenyl ring of the parent compound with 4-nitro yielded 4f, the most potent compound of the series with an IC50 value of 90 μM against Mtb NadE. Our modeling results show that these urea-sulfonamides potentially bind to the intramolecular ammonia tunnel, which transports ammonia from the glutaminase domain to the active site of the enzyme. This hypothesis is supported by data showing that, even when treated with potent inhibitors, NadE catalysis is restored when treated with exogenous ammonia. Most of these compounds also inhibited Mtb cell growth with MIC values of 19–100 μg/mL. These results improve our understanding of the SAR of the urea-sulfonamides, their mechanism of binding to the enzyme, and of Mtb NadE as a potential antitubercular drug target.
Potent and selective N-(4-sulfamoylphenyl)thiourea-based GPR55 agonists
Yrj?l?, Sari,Parkkari, Teija,Navia-Paldanius, Dina,Laitinen, Tuomo,Kaczor, Agnieszka A.,Kokkola, Tarja,Adusei-Mensah, Frank,Savinainen, Juha R.,Laitinen, Jarmo T.,Poso, Antti,Alexander, Amy,Penman, June,Stott, Lisa,Anskat, Marie,Irving, Andrew J.,Nevalainen, Tapio J.
, p. 119 - 132 (2015/11/24)
To date, many known G protein-coupled receptor 55 (GPR55) ligands are those identified among the cannabinoids. In order to further study the function of GPR55, new potent and selective ligands are needed. In this study, we utilized the screening results from PubChem bioassay AID 1961 which reports the results of Image-based HTS for Selective Agonists of GPR55. Three compounds, CID1792579, CID1252842 and CID1011163, were further evaluated and used as a starting point to create a series of nanomolar potency GPR55 agonists with N-(4-sulfamoylphenyl)thiourea scaffold. The GPR55 activity of the compounds were screened by using a commercial β-arrestin PathHunter assay and the potential compounds were further evaluated by using a recombinant HEK cell line exhibiting GPR55-mediated effects on calcium signalling. The designed compounds were not active when tested against various endocannabinoid targets (CB1R, CB2R, FAAH, MGL, ABHD6 and ABHD12), indicating compounds' selectivity for the GPR55. Finally, structure-activity relationships of these compounds were explored.
Novel Quinazoline Derivatives Bearing Various 4-Aniline Moieties as Potent EGFR Inhibitors with Enhanced Activity Against NSCLC Cell Lines
Wang, Changyan,Sun, Yajun,Zhu, Xingqi,Wu, Bin,Wang, Qiao,Zhen, Yuhong,Shu, Xiaohong,Liu, Kexin,Zhou, Youwen,Ma, Xiaodong
, p. 635 - 643 (2016/03/19)
A class of novel quinazoline derivatives bearing various C-4 aniline moieties was synthesized and biologically evaluated as potent epidermal growth factor receptor (EGFR) inhibitors for intervention of non-small-cell lung cancer (NSCLC). Most of these inhibitors are comparable to gefitinib in inhibiting these cancer cell lines, and several of them even displayed superior inhibitory activity. In particular, analogue 5b with an IC50 of 0.10 μm against the EGFR wild-type A431 cells and 5c with an IC50 of 0.001 μm against the gefitinib-sensitive HCC827 cells (EGFR del E746-A750) was identified as highly active EGFR inhibitors. It was also significant that the discovered analogue 2f, not only has high potency against the gefitinib-sensitive cells (IC50 = 0.031 μm), but also possesses remarkably improved activity against the gefitinib-resistant cells. In addition, the enzymatic assays and the Western blot analysis for evaluating the effects of the typical inhibitors indicated that these molecules strongly interfere with the EGFR target.
N-Acylated derivatives of sulfamethoxazole and sulfafurazole inhibit intracellular growth of chlamydia trachomatis
Marwaha, Sania,Uvell, Hanna,Salin, Olli,Lindgren, Anders E. G.,Silver, Jim,Elofsson, Mikael,Gylfe, ?sa
supporting information, p. 2968 - 2971 (2014/05/06)
Antibacterial compounds with novel modes of action are needed for management of bacterial infections. Here we describe a high-content screen of 9,800 compounds identifying acylated sulfonamides as novel growth inhibitors of the sexually transmitted pathogen Chlamydia trachomatis. The effect was bactericidal and distinct from that of sulfonamide antibiotics, as para-Aminobenzoic acid did not reduce efficacy. Chemical inhibitors play an important role in Chlamydia research as probes of potential targets and as drug development starting points. Copyright
Nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors: Synthesis, structure-activity relationship analysis, and biological activity
Yu, Shenghui,Zhang, Linna,Yan, Shifeng,Wang, Peng,Sanchez, Tino,Christ, Frauke,Debyser, Zeger,Neamati, Nouri,Zhao, Guisen
, p. 628 - 640 (2012/10/29)
Four series of forty-five nitrogen-containing polyhydroxylated aromatics based on caffeic acid phenethyl ester were designed and synthesized as HIV-1 integrase (IN) inhibitors. Most of these compounds inhibited IN catalytic activities in low micromolar range. Among these new analogues, compounds 9e and 9f were the most potent IN inhibitors with IC50 value of 0.7 μM against strand transfer reaction. Their key structure-activity relationships were also discussed.
