167264-91-7Relevant academic research and scientific papers
New isoleucine derived dipeptides as antiprotozoal agent: Synthesis, in silico and in vivo studies.
Ekoh, Ogechi C.,Okoro, Uchechukwu C.,Ali, Rafat,Ugwu, David I.,Okafor, Sunday N.,Ezugwu, James A.
, (2021/02/12)
The increasing emergence of malaria drug-resistant parasites and the deficiency in effective chemotherapy for trypanosomiasis represents a huge challenge in infectious disease treatment in tropical regions. As regards to developing effective antiprotozoal agents, ten new ile-gly dipeptide sulphonamide derivatives were synthesized by condensing compound (10) with (8a-j)using peptide coupling reagents. Compounds11b, 11i and 11j were most potent in clearing Trypanosome brucei in mice with 11b showing comparable activity with diminazene aceturate. In the antimalarial study, 11b was the most active compound, even better than the standard. Molecular docking result suggests good interaction between the reported compounds and the target protein. The results of haematological analysis, liver and kidney function tests showed that the compounds had no adverse effect on the blood and organs. Compound 11b stands out amongst the derivatives haven shown better activity in both the antimalarial and antitrypanosomal assay.
Synthesis, molecular docking and antimalarial activity of phenylalanine-glycine dipeptide bearing sulphonamide moiety
Ali, Rafat.,Aronimo, Babatunde. S.,Ezugwu, James. A.,Ibeji, Collins. U.,Okoro, Uchechukwu. C.,Ugwu, David. I.
, (2021/08/10)
Ten novel phenylalanine-glycine dipeptide sulphonamide conjugate were synthesized and characterized using 1HNMR, 13CNMR, FTIR and HRMS spectroscopic techniques. The in silico studies predicted better interactions of compounds with target protein residues and a higher dock score in comparison with standard drugs. The in vivo antimalarial study, hematological study, liver and kidney function test were evaluated on the synthesized compounds. Compounds 7h, 7i and 7j inhibited the parasite by 34.5–60.2% on day 4 of after-treatment exposure. Compound 7j inhibited the multiplication of the parasite by 60.2% on day 4 of after-treatment which was comparable with that of the standard drug with 68.8% inhibition at same day of after-treatment exposure.
Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer's disease
Chittiboyina, Amar G.,Doerksen, Robert J.,Modi, Gyan,Nayak, Prasanta Kumar,Pandey, Amruta,Pandey, Pankaj,Priya, Khushbu,Rai, Geeta,Shankar, Gauri,Singh, Yash Pal,Tej, Gullanki Naga Venkata Charan,Vishwakarma, Swati
, (2020/05/05)
In our overall goal to overcome the limitations associated with natural products for the management of Alzheimer's disease and to develop in-vivo active multifunctional cholinergic inhibitors, we embarked on the development of ferulic acid analogs. A systematic SAR study to improve upon the cholinesterase inhibition of ferulic acid with analogs that also had lower logP was carried out. Enzyme inhibition and kinetic studies identified compound 7a as a lead molecule with preferential acetylcholinesterase inhibition (AChE IC50 = 5.74 ± 0.13 μM; BChE IC50 = 14.05 ± 0.10 μM) compared to the parent molecule ferulic acid (% inhibition of AChE and BChE at 20 μM, 15.19 ± 0.59 and 19.73 ± 0.91, respectively). Molecular docking and dynamics studies revealed that 7a fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Asp74, Trp286, and Tyr337 in AChE and with Tyr128, Trp231, Leu286, Ala328, Phe329, and Tyr341 in BChE. Compound 7a was found to be an efficacious antioxidant in a DPPH assay (IC50 = 57.35 ± 0.27 μM), and it also was able to chelate iron. Data from atomic force microscopy images demonstrated that 7a was able to modulate aggregation of amyloid β1-42. Upon oral administration, 7a exhibited promising in-vivo activity in the scopolamine-induced AD animal model and was able to improve spatial memory in cognitive deficit mice in the Y-maze model. Analog 7a could effectively reverse the increased levels of AChE and BChE in scopolamine-treated animals and exhibited potent ex-vivo antioxidant properties. These findings suggest that 7a can act as a lead molecule for the development of naturally-inspired multifunctional molecules for the management of Alzheimer's and other neurodegenerative disorders.
Discovery of Potent, Reversible, and Competitive Cruzain Inhibitors with Trypanocidal Activity: A Structure-Based Drug Design Approach
De Souza, Mariana L.,De Oliveira Rezende Junior, Celso,Ferreira, Rafaela S.,Espinoza Chávez, Rocio Marisol,Ferreira, Leonardo L. G.,Slafer, Brian W.,Magalh?es, Luma G.,Krogh, Renata,Oliva, Glaucius,Cruz, Fabio Cardoso,Dias, Luiz Carlos,Andricopulo, Adriano D.
, p. 1028 - 1041 (2019/12/27)
A virtual screening conducted with nearly 4?000?000 compounds from lead-like and fragment-like subsets enabled the identification of a small-molecule inhibitor (1) of the Trypanosoma cruzi cruzain enzyme, a validated drug target for Chagas disease. Subsequent comprehensive structure-based drug design and structure-activity relationship studies led to the discovery of carbamoyl imidazoles as potent, reversible, and competitive cruzain inhibitors. The most potent carbamoyl imidazole inhibitor (45) exhibited high affinity with a Ki value of 20 nM, presenting both in vitro and in vivo activity against T. cruzi. Furthermore, the most promising compounds reduced parasite burden in vivo and showed no toxicity at a dose of 100 mg/kg. These carbamoyl imidazoles are structurally attractive, nonpeptidic, and easy to prepare and synthetically modify. Finally, these results further advance our understanding of the noncovalent mode of inhibition of this pharmaceutically relevant enzyme, building strong foundations for drug discovery efforts.
