An Overview of the Synthesis and Antimicrobial, Antiprotozoal, and Antitumor Activity of Thiazole and Bisthiazole Derivatives
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molecules Review An Overview of the Synthesis and Antimicrobial, Antiprotozoal, and Antitumor Activity of Thiazole and Bisthiazole Derivatives 1,2 1, 3 1 Anca-Maria Borcea , Ioana Ionut, *, Ovidiu Cris, an and Ovidiu Oniga 1 Department of Pharmaceutical Chemistry, “Iuliu Hat, ieganu” University of Medicine and Pharmacy, 41 Victor Babes, Street, 400012 Cluj-Napoca, Romania; [email protected] (A.-M.B.); [email protected] (O.O.) 2 Preclinic Department, Pharmacy Specialization, Faculty of Medicine, Lucian Blaga University of Sibiu, 2A Lucian Blaga Street, 550169 Sibiu, Romania 3 Department of Organic Chemistry, “Iuliu Hat, ieganu” University of Medicine and Pharmacy, 41 Victor Babes, Street, 400012 Cluj-Napoca, Romania; [email protected] * Correspondence: [email protected]; Tel.: +40-747-507-629 Abstract: Thiazole, a five-membered heteroaromatic ring, is an important scaffold of a large number of synthetic compounds. Its diverse pharmacological activity is reflected in many clinically approved thiazole-containing molecules, with an extensive range of biological activities, such as antibacterial, antifungal, antiviral, antihelmintic, antitumor, and anti-inflammatory effects. Due to its significance in the field of medicinal chemistry, numerous biologically active thiazole and bisthiazole deriva- tives have been reported in the scientific literature. The current review provides an overview of different methods for the synthesis of thiazole and bisthiazole derivatives and describes various com- pounds bearing a thiazole and bisthiazole moiety possessing antibacterial, antifungal, antiprotozoal, and antitumor activity, encouraging further research on the discovery of thiazole-containing drugs. Citation: Borcea, A.-M.; Ionut,, I.; Cris, an, O.; Oniga, O. An Overview of the Synthesis and Antimicrobial, Keywords: thiazole; bisthiazole; synthesis; derivatives; biological activity Antiprotozoal, and Antitumor Activity of Thiazole and Bisthiazole Derivatives. Molecules 2021, 26, 624. https://doi.org/10.3390/ 1. Introduction molecules26030624 Nitrogen-containing heterocyclic compounds play an important role in the drug dis- covery process, as approximately 75% of FDA (Food and Drug Administration)-approved Academic Editor: Baoan Song small-molecule drugs contain one or more nitrogen-based heterocycles [1]. Thiazole, or 1,3- Received: 29 December 2020 thiazole, belongs to the class of azoles and contains one sulfur atom and one nitrogen atom Accepted: 22 January 2021 at positions 1 and 3. Its diverse biological activity is reflected in a large number of clinically Published: 25 January 2021 approved thiazole-containing compounds with an extensive range of pharmacological activities. Most of these compounds are 2,4-disubstituted thiazole derivatives, and only a Publisher’s Note: MDPI stays neutral few are 2,5-disubstituted or 2,4,5-trisubstituted thiazoles [2]. with regard to jurisdictional claims in Several drugs such as sulfathiazole; aztreonam; numerous cephems (ceftaroline, cefo- published maps and institutional affil- iations. tiam, ceftibuten, cefixime, ceftriaxone, cefotaxime, ceftazidime, cefmenoxime, ceftizoxime, cefepime, cefdinir) with antibacterial effects; pramipexole with antiparkinsonian activity; edoxaban with antithrombotic effects; isavuconazole with antifungal effects; famotidine and nizatidine with antiulcer activity; meloxicam with anti-inflammatory effects; tiazofu- rin, dabrafenib, dasatinib, ixabepilone, and epothilone with antitumor effects; mirabegron Copyright: © 2021 by the authors. as a β3-adrenergic receptor agonist; nitazoxanide and thiabendazole with antiparasitic Licensee MDPI, Basel, Switzerland. effects; and febuxostat with antigout activity contain one thiazole moiety in the structure This article is an open access article (Figure1)[2–4]. distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Molecules 2021, 26, 624. https://doi.org/10.3390/molecules26030624 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 624 2 of 26 Molecules 2021, 26, x FOR PEER REVIEW 2 of 26 O O OH H2N S S N O N S H2N O N N N N HN H H O H O S N N O N S N O N S O HN O N O OH O N N O OH H O HN Cl O O N edoxaban aztreonam ceftriaxone F -O OH O N F N+ S S N S O NH N H OH N N NH N S N S OO N N N nizatidine meloxicam isavuconazole OH O H O N N S O + - O N S N O S H2N H N N N O N OH H O febuxostat mirabegron O nitazoxanide FigureFigure 1. 1.Clinical Clinical drugs drugs bearing bearing oneone thiazolethiazole ring. CompoundsCompounds bearing bearing twotwo thiazolethiazole rings, such such as as the the antitumor antitumor drug drug bleomycin, bleomycin, the the antiretroviralantiretroviral agent agent ritonavir, the the pharmacokinetic pharmacokinetic enhancer enhancer for HIV for drugs HIV drugs cobicistat, cobicistat, and andthe the antibacterial antibacterial agent agent cefditoren, cefditoren, have have been been authorized authorized on on the the pharmaceutical pharmaceutical market market (Figure(Figure2)[ 2)2 ,[2,5].5]. Figure 2. Clinical drugs bearing two thiazole rings. Figure 2. Clinical drugs bearing two thiazole rings. The high medicinal significance of this scaffold has attracted considerable attention fromThe many high researchers medicinal and significance encouraged of this the scaffolddesign and has synthesis attracted of considerable numerous thiazole attention‐ fromand many bisthiazole researchers‐containing and compounds encouraged with the designdiverse and pharmacological synthesis of numerousactivities, such thiazole- as andantibacterial bisthiazole-containing [6], antifungal compounds [7], antiprotozoal with diverse[8], antiviral pharmacological [9,10], anticancer activities, [11], anti such‐in‐ as antibacterialflammatory [[12–16],6], antifungal antioxidant [7], [17], antiprotozoal analgesic [18], [8], anticonvulsant antiviral [9,10 ],[19], anticancer antidiabetic [11 ],[20], anti- inflammatoryand antihypertensive [12–16], antioxidant[21] activities. [17 Furthermore,], analgesic [ 18thiazole], anticonvulsant compounds [ 19exhibiting], antidiabetic a prom [20‐ ], andising antihypertensive biological potential [21] activities. for the treatment Furthermore, of Alzheimer’s thiazole compounds disease [22,23] exhibiting and metabolic a promis- ingsyndrome biological [24] potential have been for reported the treatment in the scientific of Alzheimer’s literature. disease [22,23] and metabolic syndromeNowadays, [24] have research been reported in the field in theof antimicrobial scientific literature. drug design is focused on the dis‐ coveryNowadays, of novel researchtargets and in chemical the field entities of antimicrobial that possess drug antibacterial design is activity focused in on order the to dis- covery of novel targets and chemical entities that possess antibacterial activity in order to overcome the rapid development of drug resistance. The few antibiotics that have been recently approved are structurally related to older drugs, being susceptible to the same Molecules 2021, 26, x FOR PEER REVIEW 3 of 26 Molecules 2021, 26, 624 3 of 26 overcome the rapid development of drug resistance. The few antibiotics that have been recently approved are structurally related to older drugs, being susceptible to the same mechanismsmechanisms ofof resistanceresistance [[25].25]. TropicalTropical diseasesdiseases suchsuch asas ChagasChagas disease,disease, leishmaniasis,leishmaniasis, andand malaria malaria occur occur especially especially in in underdeveloped underdeveloped countries, countries, around around 266 266 million million cases cases being being reportedreported globallyglobally [[26].26]. At At the the present present time, time, only only a asmall small number number of of drugs drugs are are available available on onthe the pharmaceutical pharmaceutical market market for forthe thetreatment treatment of protozoan of protozoan infections infections [27]. [Cancer27]. Cancer remains re- mainsone of one the ofleading the leading causes causes of mortality of mortality worldwide. worldwide. The lack The of lack selectivity of selectivity and target and target speci‐ specificity,ficity, as well as well as the as thepresence presence of toxicity of toxicity and and resistance, resistance, is an is inadequate an inadequate feature feature of the of thecurrently currently available available anticancer anticancer drug drug therapy therapy [3]. [ 3Considering]. Considering all the all the above, above, there there is an is anur‐ urgentgent need need for for continuous continuous progress progress in in the the design design and development ofof anti-infectiveanti‐infective andand antitumorantitumor agents. agents. TheThe current review systematically systematically presents presents different different methods methods for for the the synthesis synthesis of thi of‐ thiazoleazole and and bisthiazole bisthiazole derivatives. derivatives. Moreover, Moreover, various various reports reports on the antimicrobial, on the antimicrobial, antipro‐ antiprotozoal,tozoal, and antitumor and antitumor activities activities of thiazoles of thiazoles and bisthiazoles, and bisthiazoles, mostly published mostly published within the withinpast 10 the years, past are 10 discussed, years, are discussed, providing providingreference for reference further for research further regarding research regarding the devel‐ theopment development of new biologically of new biologically active chemical active chemical entities. entities. 2.2. ChemistryChemistry