Antirhino/Enteroviral Vinylacetylene Benzimidazoles:  A Study of Their Activity and Oral Plasma Levels in Mice

Abstract

In an effort to find an orally bioavailable antiviral for the treatment of rhino/enteroviral infections, a series of vinylacetylene benzimidazoles (11a-o, 12, and 18a) was made. Initial studies of this class of antivirals showed that fluorine substitution on the left-hand phenyl ring in combination with the vinylacetylene moiety gave the requisite mix of physical properties to achieve good in vitro antiviral activity as well as respectable oral bioavailability in rhesus monkeys. To ascertain the generality of this finding and to broaden the scope of the structure-activity relationship (SAR), the present study concentrated on fluoro substitution of this class of molecules. The initial antiviral activity for each analogue was measured using human rhinovirus 14 (HRV-14). This served as an indicator of general antiviral activity for SAR purposes. Subsequently, the spectrum of antirhino/enteroviral activity of the more interesting analogues was evaluated through testing against a panel of seven additional rhino/enteroviruses. Broad-spectrum activity was present and consistent for all analogues tested, and it tracked closely with the antiviral activity observed against HRV-14. A simple screening protocol for oral bioavailability was established whereby compounds were administered orally to mice and plasma levels were measured. This procedure facilitated the evaluation of numerous analogues in a rapid manner. The Cmax was used as a measure of oral bioavailability to allow relative ranking of compounds. In general, fluorine substitution directly on the left-hand aromatic ring does give good oral blood levels. However, fluorine incorporation at other positions in the molecule was not as effective at maintaining either the activity or the oral plasma levels. The constructive combination of activity and oral plasma levels was maximized in three derivatives: 11a,e,g.

Crystal structure of 1-(1H-benzimidazol-2-yl)-3- (3-nitrophenyl)prop-2-en-1-one, C16H11N3O3

“…The benzimidazole derivatives showed to be also excellent inhibitors of HIV-1 reverse transcriptase [7]. The benzimidazole nucleus system, whose inestimable virtues seduced the scientific community, was moreover classified as an important pharmacophore in the discovery of modern drug [8]. From this point of view, the benzimidazole nucleus system constitutes abasic molecular scaffold in the design of new molecules of pharmacological interest.…”

Synthesis and Characterization of Oxadiazole Derivatives From Benzimidazole

“…The benzohydrazide of benzimidazole was formed by refluxing arylester of benzimidazole with methanolic hydrazine hydrate (Scheme 1). The synthesis of benzimidazole benzohydrazide Schiff bases (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) was accomplished by reacting different aldehydes with benzimidazole benzohydrazide in n-butanol in the presence of a catalytic amount of acetic acid as shown in Scheme-1. A series of new 2, 5-disubstituted-1,3,4-oxadiazoles (Table 1) The IR spectra of the synthesized compounds exhibited characteristic absorption bands at 1600 -1700 cm -1 and 3100 -3300 cm -1 due to carbonyl or C=N; and NH group, respectively.…”

“…Recently, benzimidazole derivatives have been reported as antidiabetic [1], antimicrobial [2][3], antiviral [4][5][6] antispasmodic [7] and antiasthmatic [8] agents. Similarly, oxadiazole derivatives are also recognized for their pharmacological importance and are reported to possess wide spectrum of activities such as antibacterial [9][10][11], antifungal [12] anti-inflammatory [13][14] analgesic [15], anticonvulsant [16][17], hypoglycemic [18] and anticancer [19] properties.…”

Synthesis and Catalytic Behaviors toward Styrene Polymerization of Zinc Complexes Bearing 6-Benzimidazolyl-2-aryliminoethyl Pyridine

“…如许多苯并咪唑类衍生物具有抑菌和抗病毒活 性 [8] , 用作药物及其中间体; 苯并咪唑类金属配合物还 被用作模拟酶, 作为分子探针用于基因和细胞的荧光测 定 [9] . 由于苯并咪唑环具有独特的平面结构和电子云分 布, 显示出优良的配位选择性, 成为设计烯烃聚合催化 剂的重要选择.…”