Skin Damages—Structure Activity Relationship of Benzimidazole Derivatives Bearing a 5-Membered Ring System

Abstract

In the search for scaffolds for multifunctional compounds we investigated the structure activity relationship of a class of benzimidazole derivatives bearing 5-membered ring. The newly synthesized and the already known compounds were divided into three classes that present different substituent at 5 position of the benzimidazole ring (-H, -COOH or –SO3H) and different heterocycle at position 2 (thiophene, furan or pyrrole). All the derivatives were synthesized and tested to determine their photoprotective profile against UV rays, in vitro antioxidant capacity against different radicals (DPPH and FRAP test), antifungal inhibitory activity (dermatophytes and Candida albicans), antiviral and antiproliferative activity. A Structure-Activity Relationship study indicated compound 10, bearing a pyrrole heterocycle on the benzimidazole ring, as the best multifunctional derivative of the series and as potential candidate for the development of drugs especially in case of melanoma.

Benzothiazole Derivatives as Multifunctional Antioxidant Agents for Skin Damage: Structure–Activity Relationship of a Scaffold Bearing a Five-Membered Ring System

“…As for the previously reported benzimidazole derivatives [ 31 ], position 6 unsubstituted benzothiazole compounds (compounds 8a , 9a and 10a ), in general, showed the best values of inhibition. In particular, compounds 9a and 10a showed a good inhibition of the growth of all five dermatophytes (with percentages of inhibition between 50% and 75%).…”

“…From the results obtained, it was possible to deduce that the order of protection against UVB of the newly synthesized benzothiazole derivatives is the following: furan-> pyrrole-> thiophene-derivatives, as previously seen for the benzimidazole analogue derivatives [ 31 ].…”

“…In particular, compound 10 exhibited IC 50 values towards the tested dermatophytes lower than 2 µg/mL, a good antioxidant profile in vitro (DPPH and FRAP tests), and finally showed an IC 50 equal to 9.7 µM towards human melanoma cells. To date, the mechanisms underlying this multifunctional structure–activity relationship are not known, but the interesting antioxidant and anti-melanoma multifunctional profile of compound 10 [ 31 ] led us to choose it as a lead compound to continue investigating key positions and structural features for new development.…”

“…In the present study, we decided to implement an isosteric modification to the scaffold of the lead compound, thus going from a benzimidazole nucleus to a benzothiazole, and to maintain the previously investigated five-membered rings in position 2 (pyrrole, thiophene, furan) [ 31 ], isosters of the benzene ring present in PBSA, which are of particular interest in the field of pharmaceutical chemistry for their antineoplastic, anti-inflammatory and antimicrobial profile [ 32 ]. In position 6 of the benzothiazole ring, similarly to the previous series, hydrogen, carboxylic acid and sulfonamide were inserted.…”

Nitrogen-Containing Heterocycles as Significant Molecular Scaffolds for Medicinal and Other Applications

“…These included pyrrole, thiazole, pyrazole, benzimidazole, pyridine, pyrimidine, triazine and acridine derivatives, for most of them with some biological activity being unraveled. Thus, several compounds were synthetized with a benzimidazole scaffold connected to five-membered heterocycles, among which the 2-pyrrole derivative was found the most efficient as concerns its antioxidant, antifungal and antiproliferative activity, especially against human melanoma cells [ 2 ]. New paracyclophane derivatives bearing thiazole moieties were prepared and their anticancer activities were evaluated using nine human cancer cell lines [ 3 ].…”