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

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Skin Damages—Structure Activity Relationship of Benzimidazole Derivatives Bearing a 5-Membered Ring System molecules Article Skin Damages—Structure Activity Relationship of Benzimidazole Derivatives Bearing a 5-Membered Ring System Ernestine Nicaise Djuidje 1, Elisa Durini 1, Sabrina Sciabica 2, Elena Serra 3, Jan Balzarini 4, Sandra Liekens 4, Stefano Manfredini 1 , Silvia Vertuani 1 and Anna Baldisserotto 1,* 1 Department of Life Sciences and Biotechnology, Master Course in Cosmetic Science and Technologies, University of Ferrara, 44121 Ferrara, Italy; [email protected] (E.N.D.); [email protected] (E.D.); [email protected] (S.M.); [email protected] (S.V.) 2 Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy; [email protected] 3 Aptuit, An Evotec Company, 37135 Verona, Italy; [email protected] 4 Department of Microbiology and Immunology, KU Leuven, University of Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium; [email protected] (J.B.); [email protected] (S.L.) * Correspondence: [email protected]; Tel.: +39-0532-455258 Academic Editor: György Szöllösi Received: 31 August 2020; Accepted: 17 September 2020; Published: 21 September 2020 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. Keywords: benzimidazole; UV-filter; melanoma 1. Introduction Skin is the largest body organ constituting an environmental interface by forming a protective barrier essential for homeostasis. For this reason skin is constantly exposed to exogenous and endogenous agents that could altered its functions. UV rays, microbes and pollution are responsible for external damage to the skin. However, UV is the most important factor responsible for the production of reactive oxygen species (ROS) which consequently induces the development of skin cancer and aging. So the discovery of sunscreens with combined photoprotective, antioxidant, antifungal and anti-melanoma activity remains the challenge of researchers in the pharmaceutical and cosmetic fields [1–3]. Heterocyclic compounds are fundamental building blocks of various essential natural and synthetic compounds. They play an important role in drug design thanks to their ability to act as both biomimetic and reactive pharmacophores [4]. Many of them are five- and / or six-membered heterocyclic compounds having one to three heteroatoms (especially oxygen, nitrogen and sulfur) in their structure and are significant in organic chemistry, medicinal chemistry and biochemistry [5]. Molecules 2020, 25, 4324; doi:10.3390/molecules25184324 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 16 heterocyclicMolecules 2020, 25compounds, 4324 having one to three heteroatoms (especially oxygen, nitrogen and sulfur)2 of in 17 their structure and are significant in organic chemistry, medicinal chemistry and biochemistry [5]. They are often found in large percentage in biomolecules like enzyme, vitamins and natural products [6];They for are these often reasons found inheterocyclic large percentage compounds in biomolecules remain the like challenging enzyme, vitamins issue for and the natural researchers products for the [6]; developmentfor these reasons of novel heterocyclic drugs [7]. compounds Moreover, five remain membered-rings the challenging fused issue with for benzene the researchers moiety attracted for the thedevelopment attention of of medicinal novel drugs chemists [7]. Moreover, especially five benzimidazoles membered-rings due fused to their with diverse benzene biological moiety activities attracted includingthe attention antitumor of medicinal [8–12], chemists antifungal especially [13], anthelmintics benzimidazoles [14], due anti-inflammatory to their diverse [15], biological analgesics activities [16] andincluding antiviral antitumor [17]. Compounds [8–12], antifungal belonging [13], to anthelmintics this class of heterocycles [14], anti-inflammatory are considered [15], privileged analgesics due [16] toand their antiviral broad [ 17spectrum]. Compounds pharmacological belonging activities to this class [18]. of heterocycles are considered privileged due to theirIn broad medicinal spectrum chemistry, pharmacological interest activitiesin the benzimidazole [18]. ring increased in the 1950s after the discoveryIn medicinal of 5,6-di-methyl-1- chemistry, interest (α-D-ribofuranosyl) in the benzimidazole benzimidazole ring increased as an in integral the 1950s part after of thevitamin discovery B12. Besides,of 5,6-di-methyl-1-( benzimidazoleα-D-ribofuranosyl) derivatives have benzimidazole a wide range asof anbiological integral activities part of vitaminsuch as B12.antibacterial, Besides, antimicrobial,benzimidazole antioxidant, derivatives haveanti-tuberculosis, a wide range ofantima biologicallarial, activities antiulcer, such antiallergic, as antibacterial, antidiabetic antimicrobial, as well asantioxidant, use in cardiovascular anti-tuberculosis, disease [19–22]. antimalarial, In addition antiulcer, to their antiallergic, therapeutic antidiabetic applications, as benzimidazoles well as use in arecardiovascular known for disease their [ 19UV–22 ].filtering In addition ability to their [23]. therapeutic Besides, applications, 2-phenyl-5-(pyrrolidin-1-yl)-1-(3,4,5- benzimidazoles are known trimethoxybenzyl)-1H-benzimidazolefor their UV filtering ability [23]. Besides, (PPTMB), 2-phenyl-5-(pyrrolidin-1-yl)-1-(3,4,5-trimethoxybenzyl)-1H- 2-[4-(2-{4-[1-(2-Ethoxyethyl)-1H-benzimidazol-2- yl]-1-piperidinyl}etbenzimidazole (PPTMB),hyl)phenyl]-2-methylpropanoic 2-[4-(2-{4-[1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl}ethyl)phe acid (Bilastine) and 1-[(4-chlorophenyl)methyl]- 2-methylbenzimidazolenyl]-2-methylpropanoic acid(Chlormidazole) (Bilastine) and are 1-[(4-chlorophenyl)methyl]-2-methylbenzimidazole benzimidazole analogues, respectively used in (Chlor the treatmentmidazole) of are cancer, benzimidazole allergic rhino-conjunctivitis analogues, respectively and fungal used ininfection the treatment [24]. of cancer, allergic rhino- conjunctivitis5-Membered and rings fungal including infection thiophene, [24]. 5-Membered furan and rings pyrrole including have received thiophene, considerable furan and interests pyrrole inhave the received fields of considerable medicinal interestschemistry in [25]. the fields Some of studies medicinal showed chemistry that [chalcone25]. Some and studies pyrimidine showed analoguesthat chalcone containing and pyrimidine pyrrole, furan analogues and thiophene containing have pyrrole, increased furan the and antimalarial thiophene activity have of increased several preparedthe antimalarial drugs activity[26]. They of severalalso have prepared significant drugs inflammatory, [26]. They also antineoplastic have significant and inflammatory,antimicrobial activityantineoplastic [27]. and antimicrobial activity [27]. Based on thethe biologicalbiological activities activities of of heterocyclic heterocyclic compounds compounds mentioned mentioned above above we we have have directed directed this thiswork work towards towards the study the ofstudy the structure of the activitystructure relationship activity relationship of benzimidazole of benzimidazole bearing 5-membered bearing ring 5- memberedderivatives ring and theirderivatives biological and studytheir biological as smart multifunctional study as smart compoundsmultifunctional for skin compounds damages. for To skin this damages.aim, our interest To this was aim, in developingour interest compounds was in developing starting from compounds 2-phenyl-1H-benzimidazole-5-sulphonic starting from 2-phenyl-1H- benzimidazole-5-sulphonicacid (PBSA, a commercial UVB acid filter, (PBSA, Figure a commercial1) as lead compound. UVB filter, SinceFigure the 1) isosteric as lead compound. modification Since of a thelead isosteric compound modification is a key tool of in a the lead pharmaceutical compound is sector a key for tool the in rational the pharmaceutical design of new drugs,sector changesfor the rationalhave been design made of to new the PBSAdrugs, to changes implement have this been project, made in to particular the PBSA to to positions implement 2 by this introducing project, in a particular5-member to ring positions on the phenyl2 by introducing ring and replacing a 5-member the functional ring on the group phenyl (-SO 3ringH) inand position replacing 5 of the functionalbenzimidazole group ring (-SO with3H) -COOH in position and –H.5 of Thethe threebenzimidazole series explored ring with include -COOH both alreadyand –H. known The three and seriesnewly explored synthesized include compounds. both already known and newly synthesized compounds. Figure 1. Lead compound.
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