Amino acid and Dicyclohexylurea Linked Pyrazole Analogues: Synthesis, In Silico and In Vitro Studies

Abstract

Pancreatic lipase (PL) inhibitors have received considerable attention by several researchers because of its ability to hydrolyse the triglycerides in the small intestine. This study reports the (i) synthesize of new pyrazole derivatives binding amino acid and Dicyclohexylurea (DCU), (ii) their pharmaceutical potentials-via enzyme inhibitory activity towards PL and antioxidant activities (using complementary antioxidant methods including FCR, FRAP and ORAC), (iii) the possible interactions between pyrazole compounds and PL enzyme through in silico studies, and the pharmacokinetic properties of the tetra-substituted pyrazole analogues by PreADMET. Enzyme activities with IC 50 values of the pyrazole analogues were found to be in a high range of 6.6 � 0.4 μM to 13.5 � 0.2 μM. However, antioxidant activities of the pyrazole analogues exhibited low binding affinities against FCR, FRAP, and ORAC. The pyrazole analogues with docking scores were in the range of À 7.3 to À 15.2 and their SAR analysis were demonstrated to highlight the importance of amino acid and DCU linked scaffolds. Two web tools were utilized for the purpose of predicting ADMET parameters of drugs and drug-like pyrazole analogues. These results suggested that the amino acid and DCU linked pyrazole analogues have potential as PL inhibitors.

GABA–AT Inhibitors: Design, Synthesis, Pharmacological Characterization, Molecular Docking and ADMET Studies

“…The carcinogenicity prediction of the α‐pyrazolo‐(aryl/alkyl)methyl‐ketone compounds, except 4 e and 4 g , was determined to be negative. However, only pyrazole‐isoquinoline 5 h was observed to be negative for mice data [12] . Furthermore, in this ADMET study, a hERG inhibitor dataset was collected for the design of all compounds.…”

“…The ADMET properties of the designed α‐pyrazolo‐(aryl/alkyl)methyl‐ketone ( 4 a – j ) and pyrazolo[5,1‐a]isoquinoline ( 5 a – j ) derivatives were achieved with pre‐ADMET software which is an open online tool (https://preadmet.bmdrc.kr.) [12] …”

“…However, only pyrazole-isoquinoline 5 h was observed to be negative for mice data. [12] Furthermore, in this ADMET study, a hERG inhibitor dataset was collected for the design of all compounds. The pyrazole-isoquinoline compounds 4 a-j were identified as having a medium risk of hERG inhibition.…”

“…[9] On the other hand, pyrazole scaffolds have been increasingly addressed in the scientific community because of their broad spectrum biological activities such as tranquilizing, muscle relaxant, psychoanalytic, anticonvulsant, antihypertensive, and antidepressant activities. [10][11][12][13] Many of these compounds have been developed into commercially available drugs with a wide range of pharmacological effects, including antispasmodic, hypoglycemic, anti-inflammatory, antineoplastic, analgesic, antihyperglycemic, antidepressive, and antibacterial activities. [14] The isoquinoline nucleus has been identified as a highly prevalent structural motif in numerous alkaloids found in nature, which possess potent biological activities such as topoisomerase I inhibition and anti-HIV activity.…”

Molecular Dynamics and Free Energy Landscape Study of SARS‐CoV‐2 Omicron Mpro Boswellic acid Compounds of Boswellia Serrata Inhibitors

“…In general, in the drug discovery procedure, most of the compounds failed in vitro ChemistrySelect studies due to ADMET deficiencies. Hence, PreADMET has been developed for predicting drug-likeness and toxicity, and for more information about the versatile use of this tool, we recommend the reader to follow the work of Cetin et al [28] Human intestinal absorption, cell permeability, skin permeability, blood brain barrier, plasma protein binding and toxicological properties were calculated. In our study also we have calculated the ADMET properties of all boswellic acid compounds.…”