- Synthesis, characterization, inhibition effects, and molecular docking studies as acetylcholinesterase, α-glycosidase, and carbonic anhydrase inhibitors of novel benzenesulfonamides incorporating 1,3,5-triazine structural motifs
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Some metabolic enzyme inhibitors can be used in the treatment of many diseases. Therefore, synthesis and determination of alternative inhibitors are essential. In this study, the inhibition effect of newly synthesized compounds on carbonic anhydrase (cytosolic isoforms, hCA I and hCA II), α-glycosidase (α-GLY), and acetylcholinesterase (AChE) were investigated. The possible binding mechanism of the compounds with a high inhibitory effect on the active site of the enzyme was demonstrated by molecular docking method. We investigated the inhibition effects of novel synthesized compounds (MZ1-MZ11) on metabolic enzymes such as α-GLY, AChE, and hCA I and II. The compound MZ6 for AChE, MZ8 for CA I and CA II and MZ7 for α-GLY showed a very active inhibition profile (KIs 51.67 ± 4.76 for hCA I, 40.35 ± 5.74 nM for hCA II, 41.74 ± 8.08 nM for α-GLY and 335.76 ± 46.91 nM for AChE). The novel synthesized compounds (MZ1-MZ11) have a higher enzyme (α-GLY, AChE, hCA I, and II) inhibitory potential than ACR, TAC, and AZA, respectively. The compounds may have the potential to be used as alternative medicines after further research in the treatment of many diseases such as diabetes, Alzheimer's disease, heart failure, ulcer, and epilepsy.
- Durgun, Mustafa,Lolak, Nebih,Taslimi, Parham,Akocak, Süleyman,Beydemir, ?ükrü,Gül?in, ?lhami,I??k, Mesut,Türke?, Cüneyt
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- Design, synthesis, and evaluation of HIV-1 entry inhibitors based on broadly neutralizing antibody 447-52D and gp120 V3loop interactions
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The third variable loop region (V3 loop) on gp120 plays an important role in cellular entry of HIV-1. Its interaction with the cellular CD4 and coreceptors is an important hallmark in facilitating the bridging by gp41 and subsequent fusion of membranes for transfer of viral genetic material. Further, the virus phenotype determines the cell tropism via respective co– receptor binding. Thus, coreceptor binding motif of envelope is considered to be a potent anti-viral drug target for viral entry inhibition. However, its high variability in sequence is the major hurdle for developing inhibitors targeting the region. In this study, we have used an in silico Virtual Screening and “Fragment-based” method to design small molecules based on the gp120 V3 loop interactions with a potent broadly neutralizing human monoclonal antibody, 447-52D. From the in silico analysis a potent scaffold, 1,3,5-triazine was identified for further development. Derivatives of 1,3,5-triazine with specific functional groups were designed and synthesized keeping the interaction with co-receptor intact. Finally, preliminary evaluation of molecules for HIV-1 inhibition on two different virus strains (clade C, clade B) yielded IC50 5.0 μM. The approach used to design molecules based on broadly neutralizing antibody, was useful for development of target specific potent antiviral agents to prevent HIV entry. The study reported promising inhibitors that could be further developed and studied.
- Bommakanti, Akhila,Kondapi, Anand K.,Senapathi, Jagadeesh,Vangara, Srinivas
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- Indoloxytriazines as binding molecules for the JAK2 JH2 pseudokinase domain and its V617F variant
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Small molecules that selectively bind to the pseudokinase JH2 domain over the JH1 kinase domain of JAK2 kinase are sought. Virtual screening led to the purchase of 17 compounds among which 9 were found to bind to V617F JAK2 JH2 with affinities of 40 – 300
- Newton, Ana S.,Liosi, Maria-Elena,Henry, Sean P.,Deiana, Luca,Faver, John C.,Krimmer, Stefan G.,Puleo, David E.,Schlessinger, Joseph,Jorgensen, William L.
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supporting information
(2021/07/20)
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- Novel sulfonamides incorporating 1,3,5-triazine and amino acid structural motifs as inhibitors of the physiological carbonic anhydrase isozymes I, II and IV and tumor-associated isozyme IX
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A new series of thirty s-triazinyl-substituted aminoalkylbenzenesulfonamides, incorporating a symmetric pair of amino acid moieties, is reported, together with inhibition studies of physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isofo
- Miku?, Peter,Kraj?iová, Dominika,Mikulová, Mária,Horváth, Branislav,Pecher, Daniel,Garaj, Vladimír,Bua, Silvia,Angeli, Andrea,Supuran, Claudiu T.
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p. 241 - 252
(2018/08/31)
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- Optimization and comparison of synthetic procedures for a group of triazinyl-substituted benzene-sulfonamide conjugates with amino acids
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Sulfonamides incorporating 1,3,5-triazine moieties can selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII, and XIV over cytosolic isoforms I and II. In the present work, a highly effective synthetic procedure was proposed f
- Kraj?iová, Dominika,Pecher, Daniel,Garaj, Vladimír,Miku, Peter
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- Substituted benzene sulfonamides incorporating 1,3,5-triazinyl moieties potently inhibit human carbonic anhydrases II, IX and XII
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A series of benzene sulfonamides incorporating 1,3,5-triazinyl moieties were synthesized using cyanuric chloride as starting material. Inhibition studies against human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms I, II (cytosolic) and IX, XII (transmembr
- Saluja, Amrita K.,Tiwari, Meena,Vullo, Daniela,Supuran, Claudiu T.
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supporting information
p. 1310 - 1314
(2014/03/21)
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- Sulfonamides incorporating 1,3,5-triazine moieties selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII and XIV over cytosolic isoforms i and II: Solution and X-ray crystallographic studies
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Reaction of cyanuryl chloride with d,l-amino acids and amino alcohols afforded a new series of triazinyl-substituted benzenesulfonamides incorporating amino acyl/hydroxyalkyl-amino moieties. Inhibition studies of physiologically relevant human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA I, II, IX, XII and XIV with these compounds are reported. They showed moderate-weak inhibition of the cytosolic, offtarget isozymes CA I and II, but many of them were low nanomolar inhibitors of the transmembrane, tumor-associated CA IX and XII (and also of CA XIV). The X-ray crystal structure of two of these compounds in adduct with CA II allowed us to understand the features associated with this strong inhibitory properties and possibly also their selectivity. Two of these compounds were also investigated for the inhibition of other human isoforms, that is, hCA IV, VA, VB, VI, VII and XIII, as well as inhibitors of the fungal pathogenic CAs Nce103 (Candida albicans) and Can2 (Cryptococcus neoformans), showing interesting activity. The 1,3,5-triazinyl-substituted benzenesulfonamides constitute thus a class of compounds with great potential for obtaining inhibitors targeting both α-class mammalian, tumor-associated, and β-class from pathogenic organisms CAs.
- Carta, Fabrizio,Garaj, Vladimir,Maresca, Alfonso,Wagner, Jason,Avvaru, Balendu Sankara,Robbins, Arthur H.,Scozzafava, Andrea,McKenna, Robert,Supuran, Claudiu T.
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experimental part
p. 3105 - 3119
(2011/06/25)
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- Synthesis and antitumor evaluation of a novel series of triaminotriazine derivatives
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A series of triaminotriazine derivatives (compounds 5a-f, 6a-x, and 7a-g) was designed, synthesized, and evaluated for their inhibition activities to colorectal cancer (CRC) cell lines (HCT-116 and HT-29). Most of the synthesized compounds demonstrated moderate anti-proliferatory effects on both HCT-116 and HT-29 cell lines at the concentration of 10 μM. The inhibitory activities against HCT-116 and HT-29 cell lines were discussed to develop the structure-activity relationships of this new series. Compounds 6l and 6o exhibited prominent inhibition activities toward HCT-116, with IC50s of 0.76 and 0.92 μM, respectively. The in vivo antitumor studies and pharmacokinetics of compound 6l showed that it might be a promising new hit for further development of antitumor agents.
- Zheng, Mingfang,Xu, Chenghui,Ma, Jianwei,Sun, Yan,Du, Feifei,Liu, Hong,Lin, Liping,Li, Chuan,Ding, Jian,Chen, Kaixian,Jiang, Hualiang
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p. 1815 - 1827
(2008/02/03)
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- Structure-activity relationships of novel antibacterial translation inhibitors: 3,5-Diamino-piperidinyl triazines
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Structure-activity relationships of the 3,5-diamino-piperidinyl triazine series, a novel class of bacterial translation inhibitors, are described. Optimization was focused on the triazine C-4 position in which aromatic substituents that contained electron-withdrawing groups led to potent inhibitors. The initial lack of antibacterial activity was correlated with poor cellular penetration. Whole cell antibacterial activity was achieved by linking additional aromatic moieties at the triazine C-4 position.
- Zhou, Yuefen,Sun, Zhongxiang,Froelich, Jamie M.,Hermann, Thomas,Wall, Daniel
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p. 5451 - 5456
(2007/10/03)
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- Carbonic anhydrase inhibitors: Novel sulfonamides incorporating 1,3,5-triazine moieties as inhibitors of the cytosolic and tumour-associated carbonic anhydrase isozymes I, II and IX
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A new series of aromatic benzenesulfonamides incorporating 1,3,5-triazine moieties in their molecules is reported. This series was obtained by reaction of cyanuric chloride with sulfanilamide, homosulfanilamide or 4- aminoethylbenzenesulfonamide. The prep
- Garaj, Vladimir,Puccetti, Luca,Fasolis, Giuseppe,Winum, Jean-Yves,Montero, Jean-Louis,Scozzafava, Andrea,Vullo, Daniela,Innocenti, Alessio,Supuran, Claudiu T.
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p. 3102 - 3108
(2007/10/03)
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- Carbonic anhydrase inhibitors: Synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating 1,2,4-triazine moieties
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A series of benzenesulfonamide derivatives incorporating triazine moieties in their molecules was obtained by reaction of cyanuric chloride with sulfanilamide, homosulfanilamide, or 4-aminoethylbenzenesulfonamide. The dichlorotriazinyl-benzenesulfonamides intermediates were subsequently derivatized by reaction with various nucleophiles, such as water, methylamine, or aliphatic alcohols (methanol and ethanol). The library of sulfonamides incorporating triazinyl moieties was tested for the inhibition of three physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic hCA I and II, and the transmembrane, tumor-associated hCA IX. The new compounds reported here inhibited hCA I with KIs in the range of 75-136 nM, hCA II with KIs in the range of 13-278 nM, and hCA IX with KIs in the range of 0.12-549 nM. The first hCA IX-selective inhibitors were thus detected, as the chlorotriazinyl-sulfanilamide and the bis-ethoxytriazinyl derivatives of sulfanilamide/homosulfanilamide showed selectivity ratios for CA IX over CA II inhibition in the range of 166-706. Furthermore, some of these compounds have subnanomolar affinity for hCA IX, with KIs in the range 0.12-0.34 nM. These derivatives are interesting candidates for the development of novel unconventional anticancer strategies targeting the hypoxic areas of tumors. Clear renal cell carcinoma, which is the most lethal urologic malignancy and is both characterized by very high CA IX expression and chemotherapy unresponsiveness, could be the leading candidate of such novel therapies.
- Garaj, Vladimir,Puccetti, Luca,Fasolis, Giuseppe,Winum, Jean-Yves,Montero, Jean-Louis,Scozzafava, Andrea,Vullo, Daniela,Innocenti, Alessio,Supuran, Claudiu T.
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p. 5427 - 5433
(2007/10/03)
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