Benzofuran–Morpholinomethyl–Pyrazoline Hybrids as a New Class of Vasorelaxant Agents: Synthesis and Quantitative Structure–Activity Relationship Study

Abstract

The benzofuran-morpholinomethyl-pyrazoline hybrids 4a-e, 5a-e and 6a-j were synthesized via reaction of α,β-unsaturated carbonyl compounds 3a-e with hydrazine hydrate, semicarbazide or thiosemicarbazide. Applying the Mannich reaction to 5-(5-aryl-4,5-dihydro-1H-pyrazol-3-yl)-4-methoxybenzofuran-6-ols 7a-e with morpholine hydrochloride and paraformaldehyde afforded positional isomeric 7-morpholinomethyl derivatives 4a-e and N-morpholinomethyl derivatives 8a-e. All the synthesized compounds showed significant vasodilatation properties in isolated thoracic aortic rings of rats precontracted using the standard norepinephrine hydrochloride technique. Compounds 3d, 3e, 5a-c, 6b, 6c, 6f, 6h and 6i exhibited activity (IC 50 0.3185-0.4577 mM) superior to that of prazocin (IC 50 0.487 mM), while 5d, 6j and 8c showed comparable activity (IC 50 0.4789-0.4951 mM). The quantitative structure-activity relationship study revealed a correlation between the observed vasorelaxant activities of the newly synthesized compounds and their different physicochemical parameters, especially solubility, in addition to structure connectivity and energetic quantities calculated from stored three dimensional (3D) conformations. Absorption, distribution, metabolism and elimination (ADME) evaluation showed good agreement with the biological results obtained.

Multi-Layer Identification of Highly-Potent ABCA1 Up-Regulators Targeting LXRβ Using Multiple QSAR Modeling, Structural Similarity Analysis, and Molecular Docking

“…Prior to descriptor calculation, the stochastic conformational search was performed to search the optimal geometry conformation of each energy-minimized structure. Only the lowest energy conformer of per structure was subjected to 327 diverse descriptors calculation by utilizing the QSAR module of MOE [18]. To remove redundant information, the descriptors pool was optimized by two criteria.…”

Pharmacological Perspectives of 2‐alkoxy‐3‐Cyanopyridine Scaffolds: An Up‐to‐Date Review

“…The most intriguing bioactive features linked to the benzofuran skeleton include vasodilation, analgesic, antitumor, and hypotensive effects, among others [125] . These types of Benzofuran‐pyridine hybrids 63 a – z and 63 a’ – h’ (Figure 16) were analyzed for their vasorelaxation behavior by the same author [126] .…”

Synthesis, Anticancer and Antitubercular Properties of New Chalcones and Their Nitrogen-Containing Five-Membered Heterocyclic Hybrids Bearing Sulfonamide Moiety

“…Synthetic pyrazoline derivatives have exhibited antitumor [ 35 , 36 , 37 ], antibacterial [ 38 ], immunosuppressive [ 39 ], anti-inflammatory [ 40 ], anti-diabetic [ 41 ], antidepressant [ 42 ], antimalarial [ 43 ], antiviral [ 44 ], and antihypertensive [ 45 ] activities. Particularly, the 4,5-dihydro-1 H -pyrazole-1-carbothioamides have also shown a wide variety of pharmacological properties such as anticancer [ 46 , 47 , 48 , 49 , 50 ], anticonvulsant [ 51 , 52 ], antituberculosis [ 53 ], antimicrobial [ 54 ], and anti-inflammatory [ 55 ] agents ( Figure 1 ).…”