A new therapeutic approach in Parkinson's disease: some novel quinazoline derivatives as dual selective phosphodiesterase 1 inhibitors and anti-inflammatory agents.
The increasing life expectancy in our population makes Parkinson's disease (PD) a growing public health problem. There is a great need to find a way to prevent and delay the disease. It was shown that selective phosphodiesterase 1 (PDE1) inhibitors and anti-inflammatory agents might be effective in treating PD. Therefore, a novel 1,2,9,11-tetrasubstituted-7H-thieno[2',3':4,5]pyrimido[6,1-b]-quinazolin-7-one (1-15) and 1,3,10,12-tetrasubstituted-8H-pyrido[2',3':4,5]pyrimido[6,1-b]quinazolin-8-one (16-36) derivatives were synthesized by reported method and investigated for their ability to inhibit PDE1. Most of the synthesized compounds have shown good activity against PDE1 and were less effective than 3-isobutyl-1-methylxanthine. All the compounds were also tested for their in vitro anti-inflammatory activity by carrageenan-induced oedema in rats. In addition, ulcerogenic activity was determined. The combined anti-inflammatory data from in vitro animal model showed that compounds, 9,11-dibromo-1-(2-furyl)-3-(4-tolyl)-8H-pyrido[2',3':4,5]pyrimido[6,1-b]quinazolin-8-one 23, 9,11-dibromo-1-(4-methoxy-phenyl)-3-phenyl-8H-pyrido[2',3':4,5]pyrimido[6,1-b]quinazolin-8-one 24, 9,11-dibromo-1-(4-chloro-phenyl)-3-(4-tolyl)-8H-pyrido[2',3':4,5]pyrimido[6,1-b]quinazolin-8-one 29 and 9-bromo-1-(4-chloro-phenyl)-3-(4-tolyl)-8H-pyrido[2',3':4,5]pyrimido[6,1-b]quinazolin-8-one 36 exhibited even more potent anti-inflammatory activity and low gastric ulceration incidence compare to reference standard Indomethacin. Since compound 23, 24, 29 and 36 exhibits both anti-inflammatory activity and PDE1 inhibition, it needs further detailed studies.
Laddha
Sachin S
SS
Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India.
Bhatnagar
Satyendra P
SP
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002675:Child, Preschool; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy*; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D010726:Phosphodiesterase Inhibitors; D011799:Quinazolines; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1