Design and synthesis of 3-(3-((9H-carbazol-4-yl)oxy)-2-hydroxypropyl)-2-phenylquinazolin-4(3H)-one derivatives to induce ACE inhibitory activity

• Published in: European journal of medicinal chemistry 2015-05, Vol.96, p.22-29
• Main Authors: Venkatesh, Ramineni, Kasaboina, Suresh, Gaikwad, Hanmant K., Janardhan, Sridhara, Bantu, Rajashaker, Nagarapu, Lingaiah, Sastry, G. Narahari, Banerjee, Sanjay K.
• Format: Article
• Language: English
• Subjects: ACE inhibitory activity; Angiotensin-Converting Enzyme Inhibitors - chemical synthesis; Angiotensin-Converting Enzyme Inhibitors - chemistry; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Carbazoles - chemical synthesis; Carbazoles - chemistry; Carbazoles - pharmacology; Docking studies; Dose-Response Relationship, Drug; Drug Design; Humans; Lisinopril; Models, Molecular; Molecular Structure; Peptidyl-Dipeptidase A - metabolism; Quinazolinone derivatives; Quinazolinones - chemical synthesis; Quinazolinones - chemistry; Quinazolinones - pharmacology; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.04.009

In an attempt to develop a new class of cardiovascular drugs, a series of novel carbazolyloxy phenylquinazoline derivatives 9a–g have been synthesized and evaluated as angiotensin converting enzyme (ACE) inhibitors. Most of these compounds exhibited activity as significant ACE inhibitors and three compounds (9b, 9c &9e) showed maximum inhibitory potency in enzyme based assays. To render support to the experimental results, a series of quinazolinone derivatives were docked into active site of ACE and identified the probable binding modes compared to Lisinopril. Also we have identified common pharmacophore hypothesis (AAADDRR) among the best docked conformers of most potent compounds in a series of compounds. The most potent 9b, 9c, 9e compounds shared common active site with the Lisinopril binding site and retained the key active site residue interactions. The obtained results from pharmacological and molecular modeling studies can be utilized for further optimization of identified hits for selective inhibition of ACE. Novel carbazolyloxy phenylquinazolin derivatives 9a–g have been synthesized and evaluated as angiotensin converting enzyme (ACE) inhibitors. Among them 9b, 9c and 9e showed maximum inhibitory potency and docked into active site of ACE and identified the probable binding modes compared to Lisinopril drug. [Display omitted] •Novel 3-(3-((9H-carbazol-4-yl)oxy)-2-hydroxypropyl)-2-phenylquinazolin-4(3H)-one derivatives were efficiently synthesized.•Compounds 9b, 9c, 9e shown 82.9%, 100%, 100% inhibition respectively as compared to Lisinopril drug.•Compound 9d has shown low inhibition as compared to other derivatives.•Compound 9e was well docked as compared to Lisinopril drug.