Abstract
In the present work, a facile and efficient route for the synthesis of a series of N-substituted imidazole derivatives is described. Docking studies have revealed that N-substituted imidazole derivatives based on (E)-urocanic acid may be potential antihypertensive leads. Therefore, new AT1 receptor blockers bearing either the benzyl or the biphenylmethyl moiety at the N-1 or N-3 position, either the (E)-acrylate or the propanoate fragment and their related acids at the C-4 position as well as a halogen atom at the C-5 position of the imidazole ring, were synthesized. The newly synthesized analogues were evaluated for binding to human AT1 receptor. The biological results showed that this class of molecules possesses moderate or no activity, thus not always confirming high docking scores. Nonetheless, important conclusions can be derived for their molecular basis of their mode of action and help medicinal chemists to design and synthesize more potent ones. An aliphatic group as in losartan seems to be important for enhancing binding affinity and activity.
Highlights
Angiotensin II (ANG II) is the octapeptide produced by the Renin-Angiotensin System (RAS)which plays a key role in the pathophysiology of hypertension [1,2,3,4,5]
As a continuation of our studies [18,19,20], we report on the preparation of (E)-urocanic acid-based analogues, focusing our attention on the structural modifications on the imidazole ring which would possibly enhance potency
We have demonstrated an efficient and convenient strategy for the syntheses of a series of N-benzyl and N-biphenylmethyl imidazole derivatives substituted either at the N-1 or N-3 positions of (E)-urocanic acid
Summary
Angiotensin II (ANG II) is the octapeptide produced by the Renin-Angiotensin System (RAS). Extensive Structure-Activity Relationships (SAR) and pharmacophore modeling studies [12] of ARBs, as well as the available data from literature, have illustrated the key elements required for the design of potent AT1 blockers [1]. Lipophilic substituents, such as the biphenylmethyl fragment substituted with an acidic moiety (tetrazole group, CO2H) at the. These analogues bear the (E)-acrylic acid chain of (E)-urocanic acid as well as the corresponding saturated side chain at the C-4, mimicking the carboxyterminal region of the octapeptide ANG II [21,22] and a bulky lipophilic and electron-withdrawing group such as a halogen atom at the C-5 of the imidazole ring [6,9]. The synthesized analogues were tested for their AT1 receptor affinity using binding assays
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