Thiazolo[3,2-a]benzimidazoles: Synthetic Strategies, Chemical Transformations and Biological Activities

The present review covers the recent synthetic strategies and chemical transformations of thiazolo[3,2-a]benzimidazoles and it also presents the highlights of the biological activities of these compounds.


OPEN ACCESS
In 1988, a review on fused thiazolobenzimidazoles was published by Chimirri et al. [9]. In recent years, there has been considerable interest of researchers in thiazolo [3,2-a]benzimidazoles, stimulated by their biological activities. Additionally an enormous variety of thiazolo[3,2-a]benzimidazoles with unique pharmaceutical and medicinal applications have been reported in the patent literature. These considerable biological activities and our contributions to the chemistry and biological activities of these compounds prompted us to compile the present review which deals with the recent synthetic strategies, chemical transformations and biological activities of thiazolo [3,2-a]benzimidazoles. The intention of this review is to focus mainly on publications appeared from 1989 to the end of 2009.

Chemical Transformations
In this part, each sub-title was specified for the reaction(s) of certain atom and/or its substiuent(s) in thiazolo[3,2-a]benzimidazole ring system. Chemical Abstract numbering of thiazolo[3,2a]benzimidazole atoms was considered.

Reactions of S1-C1
Microwave irradiation has been applied for a rapid and efficient synthesis of 2-arylidenethiazolo [
Condensation of 6-R-3-formylchromones 151 with thiazolone 2 by the classica method, as well as condensation in a microwave oven to synthesis compounds 152, has been studied [81] (Scheme 43). Synthesis of compounds 154 from 5-arylfuran-2-carboxaldehydes 153 have been studied in acetic anhydride, by both classical heating and under microwave assisted conditions. The beneficial effect of microwave irradiation on these condensations was found in a shortening of the reaction time and increase in the yields [82] (Scheme 43). On the other hand, dihydropyrazoles 156 were synthesized by condensation of hydrazine hydrate with arylidines 55 under microwave irradiation and solvent free conditions [84] (Scheme 44).

Reactions of C3
Compounds 197 were prepared from the reaction of 3-chloromethythiazolo [

Reactions of C6
Compound 116 was prepared from ethanone 10b and bromine in acetic acid at ambient temperature [76]. Compound 141 was prepared by the treatment of 1-(3-methylthiazolo[3,2-a]benzimidazol-2yl)ethanone (15a) under the same reaction conditions. The structure 141 was assigned for the reaction product on the basis of its single crystal X-ray diffraction [73]
3-Amino-derivatives of thiazolobenzimidazole inhibited, to different extents, the oxidation of adrenaline to adrenochrome, thus preventing formation of the superoxide radical [92]. Some synthesized thiazolobenzimidazoles showed antiparasitic activity on the helminth Trichinella spiralis in infected white mice in vitro as well as in vivo [115]. In addition, many thiazolo[3,2-a]benzimidazole derivatives are of great importance due to their antidiabetic [16], broncholytic [91], immunotropic [17] and antitrichomonal activities [116]. On the other hand, several thiazolo[3,2-a]benzimidazole derivatives are used for cancer treatment [117] or prevention of cerebral infarction [118], and the treatment and/or prevention of bone diseases [119].

COOH
The combination effect of tilomisole (Wy-18,251) with aspirin or naproxen was studied in rats with carrageenan-induced paw edema and established adjuvant arthritis was reported [126]. Tilomisole was found effective in inhibiting of alpha-interleukin 1 (IL-1)-induced cartilage proteoglycan resorption in-vitro [129].
6-Aminomethyl-substituted thiazolobenzimidazole derivatives (R = H) ( Figure 5) act as remedies for schizophrenia [136]. These compounds used in treatment or prevention of mGluR1 related diseases [137] (epilepsy, inhibition of nerve cell death, Parkinson's disease, migraine headache, anxiety disorder, cerebral infarction and neurogenic pain). 6-Aminomethyl-substituted fluorothiazolobenzimidazole derivative (R = F) as a metabotropic glutamate receptor, has excellent activity in oral administration, and is useful as a medicine [138]. The activities of thiazolo[3,2-a]benzimidazole derivatives also extend into fields other than the medicinal one; for example, they are used in magnetic recording disks [139] and in photographic fields [140][141][142].

Conclusions
In light of the literature reports cited herein, the synthetic strategies and subsequent chemical transformations of the resulting thiazolo[3,2-a]benzimidazoles provides several important classes of functionalized compounds. The simplicity and flexibility of the experimental procedures in the generation of these classes, together with the diversity of thiazolo[3,2-a]benzimidazole chemistry, make these synthetic methodologies a highly efficient and practical method for preparation of various biologically active derivatives. The investigations in the pharmaceutical filed and medicinal applications are developing quite rapidly and we hope it will bring new and useful results.