Synthesis, docking studies and in vitro evaluation of novel chalcones as potent inhibitors of phosphodiesterase 5 from human platelets and 5A from bovine recombinant

• Published in: New journal of chemistry Vol. 42; no. 17; pp. 14365 - 14385
• Main Authors: Sherikar, Amol S, Dhavale, Rakesh P, Bhatia, Manish S
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 2018; Royal Society of Chemistry
• Subjects: Aldehydes; Biocompatibility; Blood plasma; Chemical synthesis; Chemistry; Chemistry, Multidisciplinary; Condensates; Esters; Fluorine; In vitro methods and tests; Molecular docking; Nitrate esters; Nitrates; Nitration; Nitric oxide; Physical Sciences; Platelets; Receptors; Science & Technology; Substitutes; RAT; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; ENDOTHELIUM; THERAPEUTIC AGENTS; DISEASE; DRUGS; NITRIC-OXIDE; CONGESTIVE-HEART-FAILURE; DERIVATIVES
• ISSN: 1144-0546; 1369-9261
• DOI: 10.1039/c8nj02077a

A series of new nitric oxide donor chalcone moieties were synthesized and evaluated for phosphodiesterase 5 (PDE 5) and 5A (PDE 5A) inhibition potential from human plasma and bovine recombinant, respectively. Molecular docking showed an excellent binding interaction of the synthesised compounds with the receptors. The synthesis of chalcone intermediate i was carried out by reacting substituted aldehydes and acetophenones on the basis of the Claisen-Schmidt condensation reaction. A nitration reaction was carried out to obtain a substituted chalcone with phenyl nitrate and nitrate esters as the final product. The inhibitory potency of the synthesized compounds was evaluated against PDE 5 from human platelets and PDE 5A from bovine recombinant and compared with Tadalafil and a standard inhibitor. Compounds AI7 , B5 , B7 , E7 and E8 containing acetyl, nitro, carboxy methyl, hydroxy methyl functionalities exhibit a marked inhibitory effect against human platelet PDE 5. Compounds B2 , B4 , B5 , D4 , D6 and E6 containing nitro, fluorine, amino, methyl functionalities exhibit a significant inhibition of recombinant bovine PDE 5A. Compound AI7 containing the phenyl nitrate moiety and acetyl functionalities on chalcone showed 1.197 ± 3.38 μM inhibitory potency against human platelet PDE 5. Compound B2 containing amide nitrate ester and nitro functionalities on chalcone showed 1.241 ± 3.68 μM inhibitory potency against recombinant bovine PDE 5A. The biocompatibility of the synthesized compounds was checked by the in vitro haemolysis assay. All the tested compounds were observed to be non-haemolytic. Compound B2 was tested for an in vitro bacterial reverse mutation test, and found to be non-mutagenic. Chalcones with a nitric oxide (NO) donating scaffold and a variety of substituents were synthesized. A docking study was performed and molecules were evaluated for in vitro phosphodiesterase 5 and 5A inhibitory potency.