Is it possible to perform molecular hybridization between acetaminophen and nitric oxide donor molecule?

Paracetamol (Acetaminophen) belongs to the class of Non-Steroidal Anti-Infl ammatory Drugs (NSAIDs), having an analgesic, antipyretic and mild anti-infl ammatory action due to a weak inhibitory action on cyclooxygenase isoenzymes, COX-1 and COX-2. These isoenzymes are responsible for the synthesis of prostanoids that have several physiological effects, such as: vasodilation; increased renal blood fl ow; stimulation of gastric protective mucus production; inhibition of gastric acid secretion responsible for reducing acidity in gastric tissue, among other effects. Despite its benefi cial effects, the excessive use of NSAIDs is related to several adverse effects, which can alter the homeostasis of the cardiovascular, renal and gastric system [1].


Opinion
Paracetamol (Acetaminophen) belongs to the class of Non-Steroidal Anti-Infl ammatory Drugs (NSAIDs), having an analgesic, antipyretic and mild anti-infl ammatory action due to a weak inhibitory action on cyclooxygenase isoenzymes, COX-1 and COX-2. These isoenzymes are responsible for the synthesis of prostanoids that have several physiological effects, such as: vasodilation; increased renal blood fl ow; stimulation of gastric protective mucus production; inhibition of gastric acid secretion responsible for reducing acidity in gastric tissue, among other effects. Despite its benefi cial effects, the excessive use of NSAIDs is related to several adverse effects, which can alter the homeostasis of the cardiovascular, renal and gastric system [1].
The selective inhibitors of COX-2, known as COXIBS, were an alternative to control pain without having the adverse effects due to the inhibition of COX-1. Although, several reports related cardiovascular complications with long-term use of COXIBS, suggesting that specifi c benefi t/risk ratio should be considered in the prescription of this drug class [2]. Despite the notorious benefi cial effects of anti-infl ammatories drugs, their mechanism of action creates an inherent risk with its use, bringing the possibility of proposing hybrid chemical structures that can mitigate adverse effects [3].
The Nurse's Health [1] analyzed the effect of NSAIDs on 51,630 normotensive nurses aged between 44 and 69 years, pointing that women who have used acetaminophen frequently had a 20% increase in the risk of developing high blood pressure. In hypertensive patients, the long-term use of this drug class can increase up to 6 mmHg arterial pressure mean, interfering with several classes of antihypertensive drugs [4]. In addition to the cardiovascular adverse effects, the mechanism of action of acetaminophen impairs gastric defense mechanisms, providing gastric lesions.
Nitric Oxide (NO) is an intercellular messenger that plays an important role in pathological and physiological regulations.
Its antimicrobial, bactericidal, antiviral, vasodilatory and cytoprotective activity are considered fundamental for physiological homeostasis [5][6][7]. These benefi cial effects makes nitric oxide a potential ally in new drugs developments, making molecular structures capable of donating nitric oxide into study targets, such as those derived from furoxan and benzofuroxan.
Nitric oxide donor molecules were capable of decreasing the gastric membrane damage in a group of rodents submitted to ketoprofen therapy associated with an nitric oxide donor when compared to the group submitted to ketoprofen only therapy [8]. The association of furoxan or benzofuroxan derivatives with other pharmacological groups as a strategy to enhance their pharmacological effect or mitigate adverse effects has been an interesting and actual strategy. There are reports of molecular hybridization with drugs belonging to the class of -adrenergic antagonists, H2 antagonists, calcium channel modulators and non-steroidal anti-infl ammatory drugs [8]. The hybridization of NSAIDs and nitric oxide donors structures have already been proposed with the objective of making safer NSAIDs [9][10][11]. Acetaminophen and a nitric oxide donor hybrid have been synthesized using an esterifi cation reaction [12] and a study synthesized a hybrid between acetaminophen and a benzofuroxane derivate [13]. Hybridization of diclofenac and benzofuroxan derivatives have already been proposed too [14].
Therefore, it is feasible to believe that the molecular Nitric oxide donors may be the solution to prevent the majority cases of acetaminophen intoxications. It is possible to believe that the associations between NSAIDs with nitric oxid donors have the potential to make a revolution in pain treatment, since these associations have shown to be "improved" forms of NSAIDs.