5055-39-0Relevant academic research and scientific papers
Evaluation of 2-indolcarbohydrazones as potent α-glucosidase inhibitors, in silico studies and DFT based stereochemical predictions
Taha, Muhammad,Ismail, Nor Hadiani,Javaid, Kulsoom,Imran, Syahrul,Anouar, El Hassane,Wadood, Abdul,Atia-Tul-Wahab,Ali, Muhammad,Khan, Khalid Mohammed,Saad, Syed Muhammad,Rahim, Fazal,Choudhary, M. Iqbal
, p. 24 - 35 (2015)
2-Indolcarbohydrazones 1-28 were synthesized and evaluated for their α-glucosidase inhibitory potential. A varying degree of inhibitory potential with IC50 values in the range of 2.3 ± 0.11-226.4 ± 6.8 μM was observed while comparing these outcomes with the standard acarbose (IC50 = 906.0±6.3μM). The stereochemistry of ten (10) randomly selected compounds (1, 3, 6, 8, 12, 18, 19, 23, 25 and 28) was predicted by Density Functional Theory (DFT). The stability of E isomer was deduced by comparing the calculated and experimental vibration modes of νC=O, νN=C and νCH (CH in -N=CH-R). It was observed that except compound 18, all other compounds were deduced to have E configuration while molecular modeling studies revealed the key interactions between enzyme and synthesized compounds.
NEW TRIAZINOINDOLE COMPOUNDS
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Page/Page column 60, (2021/11/06)
The invention relates to novel compounds for use as inhibitors of NLRP3 inflammasone production, wherein such compounds are as defined by compounds of formula (I) and wherein the integers R1, R2, R3a and R3b are defined in the description, and where the compounds may be useful as medicaments, for instance for use in the treatment of a disease or disorder that is associated with NLRP3 inflammasome activity.
Discovery, synthesis and in combo studies of Schiff’s bases as promising dipeptidyl peptidase-IV inhibitors
Abu Khalaf, Reema,Al-Essa, Luay,Al-Shalabi, Eveen,Awad, Maha,Mefleh, Sara,Sabbah, Dima,Shabeeb, Ihsan
, (2021/09/25)
Abstract: Diabetes mellitus is a main global health apprehension. Macrovascular illnesses, neuropathy, retinopathy, and nephropathy are considered some of its severe hitches. Gliptins are a group of hypoglycemic agents that inhibit dipeptidyl peptidase-IV (DPP-IV) enzyme and support blood glucose-lowering effect of incretins. In the current research, synthesis, characterization, docking, and biological evaluation of fourteen Schiff’s bases 5a–f and 9a–h were carried out. Compound 9f revealed the best in vitro anti-DPP-IV activity of 35.7% inhibition at a concentration of 100?μM. Compounds 9c and 9f with the highest in vitro DPP-IV inhibition were subjected to the in vivo glucose-lowering test using vildagliptin as a positive inhibitor. Vildagliptin, 9c, and 9f showed significant reduction in the blood glucose levels of the treated mice after 30?min of glucose administration. Moreover, induced fit docking showed that these derivatives accommodated the enzyme binding site with comparable docking scores. Schiff’s bases can serve as promising lead for the development of new DPP-IV inhibitors. Graphical Abstract: [Figure not available: see fulltext.].
Design, synthesis, anticancer activity, and solid lipid nanoparticle formulation of indole-and benzimidazole-based compounds as pro-apoptotic agents targeting bcl-2 protein
Nagy, Manar I.,Darwish, Khaled M.,Kishk, Safaa M.,Tantawy, Mohamed A.,Nasr, Ali M.,Qushawy, Mona,Swidan, Shady A.,Mostafa, Samia M.,Salama, Ismail
, p. 1 - 37 (2021/02/16)
Cancer is a multifactorial disease necessitating identification of novel targets for its treat-ment. Inhibition of Bcl-2 for triggered pro-apoptotic signaling is considered a promising strategy for cancer treatment. Within the current work, we aimed to design and synthesize a new series of benzimidazole-and indole-based derivatives as inhibitors of Bcl-2 protein. The market pan-Bcl-2 inhibitor, obatoclax, was the lead framework compound for adopted structural modifications. The obatoclax’s pyrrolylmethine linker was replaced with straight alkylamine or carboxyhydrazine methylene linkers providing the new compounds. This strategy permitted improved structural flexibility of synthesized compounds adopting favored maneuvers for better fitting at the Bcl-2 major hydrophobic pocket. Anti-cancer activity of the synthesized compounds was further investigated through MTT-cytotoxic assay, cell cycle analysis, RT-PCR, ELISA and DNA fragmentation. Cytotoxic results showed compounds 8a, 8b and 8c with promising cytotoxicity against MDA-MB-231/breast cancer cells (IC50 = 12.69 ± 0.84 to 12.83 ± 3.50 μM), while 8a and 8c depicted noticeable activities against A549/lung adenocarcinoma cells (IC50 = 23.05 ± 1.45 and 11.63 ± 2.57 μM, respectively). The signaling Bcl-2 inhibition pathway was confirmed by molecular docking where significant docking energies and interactions with key Bcl-2 pocket residues were depicted. Moreover, the top active compound, 8b, showed significant upregulated expression levels of pro-apoptotic/anti-apoptotic of genes; Bax, Bcl-2, caspase-3,-8, and-9 through RT-PCR assay. Improving the compound’s pharmaceutical profile was undertaken by introducing 8b within drug-solid/lipid nanoparticle formulation prepared by hot melting homogenization technique and evaluated for encapsulation efficiency, particle size, and zeta potential. Significant improvement was seen at the compound’s cytotoxic activity. In conclusion, 8b is introduced as a promising anti-cancer lead candidate that worth future fine-tuned lead optimization and development studies while exploring its potentiality through in-vivo preclinical investigation.
Design, synthesis, and antimicrobial activity of certain new indole-1,2,4 triazole conjugates
Al-Mutairi, Maha S.,Al-Wabli, Reem I.,Alsulami, Mona A.,Attia, Mohamed I.,Bukhari, Sarah I.,Moubayed, Nadine M. S.
, (2021/05/28)
The increasing prevalence of microbial infections and the emergence of resistance to the currently available antimicrobial drugs urged the development of potent new chemical entities with eminent pharmacokinetic and/or pharmacodynamic profiles. Thus, a series of new indole-triazole conjugates 6a-u was designed and synthesized to be assessed as new antimicrobial candidates using the diameter of the inhibition zone and minimum inhibitory concentration assays against certain microbial strains. Their in vitro antibacterial evaluation revealed good to moderate activity against most of the tested Gram-negative strains with diameter of the inhibition zone (DIZ) values in the range of 11–15 mm and minimum inhibition concentration (MIC) values around 250 μg/mL. Meanwhile, their in vitro antifungal evaluation demonstrated a potent activity against Candida tropicalis with MIC value as low as 2 μg/mL for most of the tested compounds. Moreover, compound 6f is the most potent congener with an MIC value of 2 μg/mL against Candida albicans.
4-Alkyl-1,2,4-triazole-3-thione analogues as metallo-β-lactamase inhibitors
Gavara, Laurent,Legru, Alice,Verdirosa, Federica,Sevaille, Laurent,Nauton, Lionel,Corsica, Giuseppina,Mercuri, Paola Sandra,Sannio, Filomena,Feller, Georges,Coulon, Rémi,De Luca, Filomena,Cerboni, Giulia,Tanfoni, Silvia,Chelini, Giulia,Galleni, Moreno,Docquier, Jean-Denis,Hernandez, Jean-Fran?ois
supporting information, (2021/06/15)
In Gram-negative bacteria, the major mechanism of resistance to β-lactam antibiotics is the production of one or several β-lactamases (BLs), including the highly worrying carbapenemases. Whereas inhibitors of these enzymes were recently marketed, they only target serine-carbapenemases (e.g. KPC-type), and no clinically useful inhibitor is available yet to neutralize the class of metallo-β-lactamases (MBLs). We are developing compounds based on the 1,2,4-triazole-3-thione scaffold, which binds to the di-zinc catalytic site of MBLs in an original fashion, and we previously reported its promising potential to yield broad-spectrum inhibitors. However, up to now only moderate antibiotic potentiation could be observed in microbiological assays and further exploration was needed to improve outer membrane penetration. Here, we synthesized and characterized a series of compounds possessing a diversely functionalized alkyl chain at the 4-position of the heterocycle. We found that the presence of a carboxylic group at the extremity of an alkyl chain yielded potent inhibitors of VIM-type enzymes with Ki values in the μM to sub-μM range, and that this alkyl chain had to be longer or equal to a propyl chain. This result confirmed the importance of a carboxylic function on the 4-substituent of 1,2,4-triazole-3-thione heterocycle. As observed in previous series, active compounds also preferentially contained phenyl, 2-hydroxy-5-methoxyphenyl, naphth-2-yl or m-biphenyl at position 5. However, none efficiently inhibited NDM-1 or IMP-1. Microbiological study on VIM-2-producing E. coli strains and on VIM-1/VIM-4-producing multidrug-resistant K. pneumoniae clinical isolates gave promising results, suggesting that the 1,2,4-triazole-3-thione scaffold worth continuing exploration to further improve penetration. Finally, docking experiments were performed to study the binding mode of alkanoic analogues in the active site of VIM-2.
Synthesis under microwaves irradiation, structure elucidation, docking study for inhibiting COVID-19 and DFT calculations of novel azoles incorporated indole moiety
Al-Qurashi, Nadia T.,Althagafi, Ismail,Farghaly, Thoraya A.,Farooq, Umar,Ibrahim, Mona H.
, (2021/08/19)
In short reaction time with excellent yield, we designed and synthesized a series of indole linked azole ring at position-2 as thiazole and pyrazole moieties under microwaves irradiation. The structures and mechanistic pathways were discussed in this context using all available spectroscopic techniques. On the other hand, in some cases, the spectral data failed to differentiate and confirm the actual structure of some reactions, thus, we used the functional density theory calculations performed at the B3LYP/6-31G (d, p) level of the theory in order to distinguish the most stable derivative. The antimicrobial activity of selected derivatives showed moderate to good activity against some strains of bacteria and fungi while, indole-linked-pyrazole derivative 20 showed superior antifungal activity against Aspergillus fumigatus. Moreover, the pharmacokinetic and pharmacodynamic profiles were calculated and studied for all synthesized indole derivatives. Using the Molecular docking to study the affinities of the new derivatives to binding site of three SARS-CoV-2 enzymes (polymerase, helicase, and methyltransferase) to investigate their antiviral activity against SARS-CoV-2. The results indicated that all compounds have excellent energy level; docking scores from -6.5 to – 8.7 Kcal/mol in comparison with ligand score -5.5 Kcal/mol.
FLOW CHEMISTRY SYNTHESIS OF ISOCYANATES
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Paragraph 0175; 0186-0187; 0261-0262, (2021/06/22)
The disclosure provides, inter alia, safe and environmentally-friendly methods, such as flow chemistry, to synthesize isocyanates, such as methylene diphenyl diisocyanate, toluene diisocyanate, hexamethylene diisocyanate, isophorone diisocyanate, and tetramethylxylene diisocyanate.
Synthesis, biological evaluation and in silico studies of certain oxindole–indole conjugates as anticancer CDK inhibitors
Abdel-Aziz, Hatem A.,Al-Ansary, Ghada H.,Al-Warhi, Tarfah,Aljaeed, Nada,Ayyad, Rezk R.,El Kerdawy, Ahmed M.,Eldehna, Wagdy M.,Ismael, Omnia E.
supporting information, (2020/05/05)
On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole–indole conjugates (6a–i and 9a–f) and carbocycle–indole conjugates (11a,b) as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole–indole conjugates, except 6i, 9b, and 9c efficiently affected the growth of the human breast cancer MCF-7 (IC50: 0.39 ± 0.05–21.40 ± 1.58 μM) and/or MDA-MB-231 (IC50: 1.03 ± 0.04–22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds 11a,b) diminished the anti-proliferative activity. In addition, hybrids 6e and 6f displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (6a–h, 9a, and 9e) were investigated for their potential inhibitory action toward CDK4. Hybrids 6a and 6e displayed good CDK4 inhibitory activity with IC50s equal 1.82 and 1.26 μM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids 6a and 6e as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.
Three indole derived azo-azomethine dyes as effective chemosensors for F-ion and trace water detection
Yang, Xiaofeng,Zhu, Fengqiao,Li, Yexin,Yan, Mei,Cui, Yu,Sun, Guoxin
, p. 870 - 879 (2020/08/28)
Three new dyes 13 derived from indol-carbohydrazide and azo-azomethine for the optical detection of F- ion have been developed. Dye 1 was found to be an effective colorimetric sensor for F- ion response with over 250 nm red-shift. Moreover, the resultant dye...HF2- complex (dye-F) could be successfully used as a secondary sensor for analyzing trace water in aprotic organic solvents especially in acetonitrile with a low limit of detection. In addition to detection of low-level water content in solution, test paper incorporated with 1-F complex or 2-F complex was well developed for naked-eye detection of water content in four organic solvents as mentioned above. Importantly, the test paper prepared by introducing 1-F complex or 2-F complex could be developed to prepare an ink-free rewritable paper by using water as the sole trigger. Furthermore, the same test paper could still work for many cycles without obvious loss in color quality.
