Multifunctional Isosteric Pyridine Analogs-Based 2-Aminothiazole: Design, Synthesis, and Potential Phosphodiesterase-5 Inhibitory Activity

Abstract

The elaboration of new small molecules that target phosphodiesterase enzymes (PDEs), especially those of type 5 (PDE5), is an interesting and emerging topic nowadays. A new series of heterocycle-based aminothiazoles were designed and synthesized from the key intermediate, 3-oxo-N-(thiazol-2-yl)butanamide (a PDE5 inhibitor that retains its amidic function), as an essential pharmacophoric moiety. The PDE5 inhibitors prevent the degradation of cyclic guanosine monophosphate, thereby causing severe hypotension as a marked side effect. Hence, an in vivo testing of the target compounds was conducted to verify its relation with arterial blood pressure. Utilizing sildenafil as the reference drug, Compounds 5, 10a, and 11b achieved 100% inhibitions of PDE5 without significantly lowering the mean arterial blood pressures (115.95 ± 2.91, 110.3 ± 2.84, and 78.3 ± 2.57, respectively). The molecular docking study revealed that the tested compounds exhibited docking poses that were similar to that of sildenafil (exploiting the amide functionality that interacted with GLN:817:A). The molecular shape and electrostatic similarity revealed a comparable physically achievable electrostatic potential with the reference drug, sildenafil. Therefore, these concomitant results revealed that the tested compounds exerted sildenafil-like inhibitory effects (although without its known drawbacks) on blood circulation, thus suggesting that the tested compounds might represent a cornerstone of beneficial drug candidates for the safe treatment for erectile dysfunction.

One-Pot Syntheses of Substituted 2-Aminothiazoles and 2-Aminoselenazoles via Meerwein Arylation of Alkyl Vinyl Ketones

“…Thus, the 2-aminothiazole partial structure is a significant pharmacophore 1 of a broad variety of therapeutics and drugs, covering the range from antitumor, 2 3 4 5 6 antibacterial, 7 antitubercular, 8 anti-leishmanial, 9 and antioxidant 10 agents to phosphodiesterase-5 antagonists. 11 As examples, Figure 1 shows some structures of clinical drugs bearing the 2-aminothiazole pharmacophore. 2-Aminothiazoles are also utilized as components of azo dyes, 12 corrosion inhibitors, 13 and fluorophores.…”

Synthesis, Characterization, Antimicrobial Assessments, Potential Antioxidant and Molecular Docking Studies of Polyfunctional Substituted Azoles, Azines, and their Analogs linked Sulfamethoxazole moiety

“…Pyrimidines are also used as an antitumor [7], anti-inflammatory [8], analgesic [8], antiviral [9,10,11], antineoplastic [12], antitubercular [13,14], and diuretic agents [15]. Also, pyridines, triazines, thiophenes, pyrazoles, and their analogues have many important applications [16][17][18]. The importance of such compounds lies in their diverse pharmaceutical activities, namely antimicrobial [20], antidiabetic [21], antiviral [22], anti-inflammatory and analgesic [23], activities.…”