A facile synthesis and dual inhibitor activity of novel synthesized quinazoline hydrazine-thiazoliine based Drugs

Abstract

Inflammation is a pervasive phenomenon that operates during severe perturbations of homeostasis, such as infection, injury, and exposure to contaminants, and is triggered by innate immune receptors that recognize pathogens and damaged cells. The long-term administration of nonsteroidal anti-inflammatory drugs (NSAIDs) is often limited by the emergence of gastrointestinal or cardiovascular complications . There is an indication that COX inhibition by NSAIDs enhanced synthesis of leukotrienes that occur by shunting the arachidonic acid metabolism towards the 5-lipoxygenase pathway. Dual inhibition of COX and 5 -LOX act by blocking the formation of both prostaglandins and leukotriene but do not affect lipoxin formation. Such combined inhibition avoids some of the disadvantages of selective COX-2 inhibitors and spares the gastrointestinal mucosa. 2 substituted quinazolin-4 (3H)-one was reacted with the thiosemicarbazides through the nucleophilic addition reaction to produce the quinazoline thiosemicarbazides (compound 1 & II) and the addition of various bromoketones to the com pound I & II were undergone the cyclizasation reaction to yield 2-(4-(4-substituted) thiazol-2 (3H)-ylidene)-1-(2-substituted quinazolin-4 (3H)-ylidene)hydrazine. According to the acute oral toxicity evaluation, 20 mg/kg doses of synthesized compounds were administered orally to the rats for this study. The in-vivo acute anti-inflammatory activity using a carrageenan-induced hind paw edema model and acute ulcerogenicity were studied in albino rats to show their dual inhibitor Cyclooxygenase/5 Lipooxygenase (COX/5LOX) activity. After 6h also, almost all the newly synthesized compounds showed 51-60 % edema inhibition than the standard drug and did not show any redness for ulcerogenicity. They act by blocking the formation of both prostaglandins and leucotrienes but do not affect lipoxin formation. Such combined inhibition avoids some of the disadvantages of selective COX-2 inhibitors and spares the gastrointestinal  mucosa.The novel  synthesised compounds can serve as COX/5 LOX dual inhibitor to reduce the burden of society.