- Synthesis, characterization, in vitro tissue-nonspecific alkaline phosphatase (TNAP) and intestinal alkaline phosphatase (IAP) inhibition studies and computational evaluation of novel thiazole derivatives
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Alkaline phosphatases (APs) are a class of homodimeric enzymes which physiologically possess the dephosphorylation ability. APs catalyzes the hydrolysis of monoesters into phosphoric acid which in turn catalyze a transphosphorylation reaction. Thiazoles are nitrogen and sulfur containing aromatic heterocycles considered as effective APs inhibitors. In this context, the current research paper presents the successful synthesis, spectroscopic characterization and in vitro alkaline phosphatase inhibitory potential of new thiazole derivatives. The structure activity relationship and molecular docking studies were performed to find out the binding modes of the screened compounds with the target site of tissue non-specific alkaline phosphatase (h-TNAP) as well as intestinal alkaline phosphatase (h-IAP). Compound 5e was found to be potent inhibitor of h-TNAP with IC50 value of 0.17 ± 0.01 μM. Additionally, compounds 5a and 5i were found to be highly selective toward h-TNAP with IC50 values of 0.25 ± 0.01 μM and 0.21 ± 0.02 μM, respectively. In case of h-IAP compound 5f was the most potent inhibitor with IC50 value of 1.33 ± 0.10 μM. The most active compounds were resort to molecular docking studies on h-TNAP and h-IAP to explore the possible binding interactions of enzyme-ligand complexes. Molecular dynamic simulations were carried out to investigate the overall stability of protein in apo and holo state.
- Aziz, Hamid,Iqbal, Jamshed,Mahmood, Abid,Pelletier, Julie,Sévigny, Jean,Saeed, Aamer,Shafiq, Zahid,Zaib, Sumera
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- Design, synthesis and molecular docking studies of some thiazole clubbed heterocyclic compounds as possible anti-infective agents
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The present work describes synthesis of a series of 5-((1-(4-(4-chlorophenyl)thiazol-2-yl)-3- aryl-1H-pyrazol-4-yl)methylene)-2-(arylimino)thiazolidin-4-one derivatives and their molecular docking and biological evaluation as possible antimalarial, anthelmintic and antimicrobial agents. The synthesis of compounds has been accomplished by adopting suitable synthetic methods. Structures of newly synthesized compounds were characterized and authenticated by spectral methods such as IR, 1H-NMR and mass spectra. Synthesized compounds were screened for their in vitro antimicrobial activity against selected bacterial strains and fungal strains viz. B. subtilis, S. aureus, E. coli, P. fluorescens, C. albicans, C. glabrata and antimalarial studies against P. falciparum. Titled compounds were also tested against Pheretima posthuma (earthworm) for their anthelmintic activity. Molecular docking was done to study the binding modes of the potent compounds against Escherichia coli (PDB ID: 1AB4) and Candida P450DM (PDB ID: 1EA1) enzymes. The results revealed that all the compounds exhibited moderate to significant antimicrobial activities. Antimalarial activity screening revealed that one compound 8i showed significant antimalarial activity with of IC50; 0.59 μg/mL as compared to standard drugs chloroquine (IC50= 0.020 μg/mL) and quinine (IC50; 0.268 μg/mL). The most active compound exhibited the mean paralysis time of 19.2 ± 0.9 min and mean death time of 31.7 ± 2.5 min. It can be concluded that some of the synthesized compounds have remarkable antiinfective, antimalarial and anthelmintic activity and are suitable candidates for further scientific exploration.
- Sharma, Prabodh Chander,Saini, Anil,Bansal, Kushal Kumar,Sharma, Archana,Gupta, Girish Kumar
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p. 716 - 726
(2018/07/13)
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- Synthesis of some thiazole clubbed heterocycles as possible antimicrobial and anthelmintic agents
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Present study describes synthesis and biological evaluation of five 5-((1-(4-(4-chlorophenyl)thiazol-2- yl)-3-aryl-1H-pyrazol-4-yl)methylene)-2-(aryllimino)thiazolidin-4-one derivatives as antiinfective agents. Synthesized compounds were screened for thei
- Saini, Anil,Bansal, Kushal K.,Sharma, Prabodh C.
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p. 303 - 310
(2019/01/18)
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- Synthesis of a novel series of thiazole-based histone acetyltransferase inhibitors
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Acetylation, which targets a broad range of histone and non-histone proteins, is a reversible mechanism and plays a critical role in eukaryotic genes activation/deactivation. Acetyltransferases are very well conserved through evolution. This allows the use of a simple model organism, such as budding yeast, for the study of their related processes and to discover specific inhibitors. Following a simple yeast-based chemogenetic approach, we have identified a novel HAT (histone acetyltransferase) inhibitor active both in vitro and in vivo. This new synthetic compound, 1-(4-(4-chlorophenyl)thiazol-2- yl)-2-(propan-2-ylidene)hydrazine, named BF1, showed substrate selectivity for histone H3 acetylation and inhibitory activity in vitro on recombinant HAT Gcn5 and p300. Finally, we tested BF1 on human cells, HeLa as control and two aggressive cancer cell lines: a neuroblastoma from neuronal tissue and glioblastoma from brain tumour. Both global acetylation of histone H3 and specific acetylation at lysine 18 (H3AcK18) were lowered by BF1 treatment. Collectively, our results show the efficacy of this novel HAT inhibitor and propose the utilization of BF1 as a new, promising tool for future pharmacological studies.
- Secci, Daniela,Carradori, Simone,Bizzarri, Bruna,Bolasco, Adriana,Ballario, Paola,Patramani, Zoi,Fragapane, Paola,Vernarecci, Stefano,Canzonetta, Claudia,Filetici, Patrizia
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p. 1680 - 1689
(2014/03/21)
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- Evaluation of a large library of (thiazol-2-yl)hydrazones and analogues as histone acetyltransferase inhibitors: Enzyme and cellular studies
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Recently we described some (thiazol-2-yl)hydrazones as antiprotozoal, antifungal and anti-MAO agents as well as Gcn5 HAT inhibitors. Among these last compounds, CPTH2 and CPTH6 showed HAT inhibition in cells and broad anticancer properties. With the aim to identify HAT inhibitors more potent than the two prototypes, we synthesized several new (thiazol-2-yl)hydrazones including some related thiazolidines and pyrimidin-4(3H)-ones, and we tested the whole library existing in our lab against human p300 and PCAF HAT enzymes. Some compounds (1x, 1c', 1d', 1i' and 2m) were more efficient than CPTH2 and CPTH6 in inhibiting the p300 HAT enzyme. When tested in human leukemia U937 and colon carcinoma HCT116 cells (100 μM, 30 h), 1x, 1i' and 2m gave higher (U937 cells) or similar (HCT116 cells) apoptosis than CPTH6, and were more potent than CPTH6 in inducing cytodifferentiation (U937 cells).
- Carradori, Simone,Rotili, Dante,De Monte, Celeste,Lenoci, Alessia,D'Ascenzio, Melissa,Rodriguez, Veronica,Filetici, Patrizia,Miceli, Marco,Nebbioso, Angela,Altucci, Lucia,Secci, Daniela,Mai, Antonello
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p. 569 - 578
(2014/06/09)
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