Thiazoles and Thiazolidinones As COX/LOX Inhibitors
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molecules Review Thiazoles and Thiazolidinones as COX/LOX Inhibitors Konstantinos Liaras ID , Maria Fesatidou ID and Athina Geronikaki * Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University, 54124 Thessaloniki, Greece; [email protected] (K.L.); [email protected] (M.F.) * Correspondence: [email protected]; Tel.: +30-231-099-7616 Academic Editor: Derek J. McPhee Received: 28 February 2018; Accepted: 16 March 2018; Published: 18 March 2018 Abstract: Inflammation is a natural process that is connected to various conditions and disorders such as arthritis, psoriasis, cancer, infections, asthma, etc. Based on the fact that cyclooxygenase isoenzymes (COX-1, COX-2) are responsible for the production of prostaglandins that play an important role in inflammation, traditional treatment approaches include administration of non-steroidal anti-inflammatory drugs (NSAIDs), which act as selective or non-selective COX inhibitors. Almost all of them present a number of unwanted, often serious, side effects as a consequence of interference with the arachidonic acid cascade. In search for new drugs to avoid side effects, while maintaining high potency over inflammation, scientists turned their interest to the synthesis of dual COX/LOX inhibitors, which could provide numerous therapeutic advantages in terms of anti-inflammatory activity, improved gastric protection and safer cardiovascular profile compared to conventional NSAIDs. Thiazole and thiazolidinone moieties can be found in numerous biologically active compounds of natural origin, as well as synthetic molecules that possess a wide range of pharmacological activities. This review focuses on the biological activity of several thiazole and thiazolidinone derivatives as COX-1/COX-2 and LOX inhibitors. Keywords: thiazole; thiazolidinone; COX; LOX; anti-inflammatory 1. Introduction Inflammation is a natural process that is connected to various conditions and disorders such as arthritis, psoriasis, cancer, infections, asthma, etc. Based on the fact that cyclooxygenase isoenzymes (COX-1, COX-2) are responsible for the production of prostaglandins that play an important role in inflammation, traditional treatment approaches include administration of nonsteroidal anti-inflammatory drugs (NSAIDs), which act as selective or non-selective COX inhibitors [1–3]. It is well established that COX-1 inhibitors, such as acetylsalicylic acid, induce gastrointestinal irritation, due to the fact that this particular COX isoenzyme is responsible for the production of gastroprotective prostaglandins. Moreover, this group of drugs can be responsible for increased bleeding diathesis resulted from inhibiting COX-1 catalyzed production of thromboxane A2 (TXA2). The severity of side effects caused by COX-1 or combined COX-1/COX-2 inhibitors (e.g., ibuprofen) concentrated the scientific interest on the production of selective COX-2 inhibitors, inspired by evidence supporting over-expression of this particular isoenzyme during inflammatory conditions. However, the hope for this new generation of drugs to be more effective than their predecessors and with less severe side effects was overshadowed by their association with increased myocardial infarction risk and cardiovascular thrombotic events. These severe side effects are mainly a result of inhibition of COX-2 catalyzed production of prostacyclin (PGI2), a prostaglandin possessing vasodilatory and antiaggregatory properties [4–7]. Molecules 2018, 23, 685; doi:10.3390/molecules23030685 www.mdpi.com/journal/molecules Molecules 2018, 23, 685 2 of 21 Molecules 2018, 23, x 2 of 22 In search for new drugs to avoid side effects, while maintaining high potency over inflammation, In search for new drugs to avoid side effects, while maintaining high potency over scientistsinflammation, turned theirscientists interest turned on leukotrienestheir interest andon leukotrienes lipoxins, which and lipoxins, are produced which via are the produced lipoxygenase via (LOX)the pathwaylipoxygenase and are(LOX) associated pathway with and various are associated procedures with such various as leucocytes procedures activation such as andleucocytes adhesion to vascularactivation endothelium, and adhesion bronchial to vascular asthma endothelium, pathogenesis, bronchial formation asthma ofpathogenesis, edema and gastricformation mucosa of damageedema [ 2and,8,9 gastric]. Consequently, mucosa damage dual [2,8,9]. COX/LOX Consequently, inhibitors dual could COX/LOX provide inhibitors numerous could therapeutic provide advantagesnumerous in termstherapeutic of anti-inflammatory advantages in activity,terms of improved anti-inflammatory gastric protection activity, and improved safer cardiovascular gastric profileprotection compared and tosafer conventional cardiovascular NSAIDs. profile Therefore, compared in theto recentconventional years, aNSAIDs. notable researchTherefore, effort in the in the fieldrecent of dual-acting years, a notable COX/LOX research inhibitors effort within the very field promising of dual-acting results COX/LO has beenX observed inhibitors [10 with,11]. very One of thepromising eminent compounds results has been that wasobserved a result [10,11]. of the One above-mentioned of the eminent scientificcompounds effort that is was licofelone a result (Figure of the 1), a dualabove-mentioned COX/5-LOX scientific inhibitor effort that wasis licofelone under production (Figure 1), a by dual the COX/5-LOX pharmaceutical inhibitor industry, that was with under mixed resultsproduction of phase by III the of pharmaceutical clinical trials for industry, osteoarthritis with mi patientsxed results [12]. of While phase being III of a clinical non-selective trials for COX inhibitor,osteoarthritis it simultaneously patients [12]. inhibits While 5-lipoxygenasebeing a non-sele activatingctive COX protein inhibitor, (FLAP) it simultaneously [13]. It was proved inhibits that polypharmacological5-lipoxygenase activating activity protein of licofelone (FLAP) is [13]. supported It was byproved inhibition that polypharmacological of mPGES-1 [14]. Recently, activity it of was licofelone is supported by inhibition of mPGES-1 [14]. Recently, it was found that licofelone found that licofelone modulates neuroinflammation in the chronic phase of spinal cord injury [15]. It is modulates neuroinflammation in the chronic phase of spinal cord injury [15]. It is believed that this believed that this action is due to elevation of levels of endogenous anti-oxidants and anti-inflammatory action is due to elevation of levels of endogenous anti-oxidants and anti-inflammatory metabolites metabolites in the lesion site. In another publication, the effect of licofelone in intracerebroventricular in the lesion site. In another publication, the effect of licofelone in intracerebroventricular streptozotocin–inducedstreptozotocin–induced cognitive cognitive deficitdeficit inin ratsrats was observed [16]. [16]. Two Two other other compounds compounds that that are are mentionedmentioned in thein literaturethe literature as dual as COX/LOX dual COX/LOX inhibitors inhibitors are thiazol-4(5 are thiazol-4(5H)-one derivatives:H)-one derivatives: darbufelone anddarbufelone CI-987 (Figure and 1CI-987)[17]. (Figure 1) [17]. FigureFigure 1. 1.Chemical Chemical structures structures ofof Licofelone, Darbufelone Darbufelone and and CI-987. CI-987. It is well established that compounds that contain sulfur atoms play a significant role in living organismsIt is well [18,19]. established In particular, that compounds thiazole thatis a containwell-known sulfur heterocyclic atoms play aromatic a significant compound role in that living organismscontains [ 18sulfur,19]. and In particular, nitrogen atoms thiazole at ispositions a well-known 1 and heterocyclic3 of its five-member aromatic ring, compound respectively that contains [20]. sulfurΤhiazole and nitrogen moiety atomscan be atfound positions in numerous 1 and 3 of biologic its five-memberally active ring, compounds respectively of natural [20]. Thiazole origin (e.g., moiety canthiamine be found [19,20], in numerous mycothiazole biologically [21], cystothiazole active compounds C [22], as well of natural as synthetic origin molecules (e.g., thiamine possessing [19 a,20 ], mycothiazolewide range [ 21of], cystothiazolepharmacological C [22activities], as well such as syntheticas antimicrobial molecules [23–28], possessing antiviral a wide [29,30], range of pharmacologicalantitubercular [23,31], activities anti-inflammatory such as antimicrobial [32–34], anxiolytic [23–28], antiviral[35], anaesthetic [29,30], antitubercular[36], anticonvulsant [23,31 ], anti-inflammatory[37–40], etc.). There [32 is–34 a ],large anxiolytic number [ 35of ],known anaesthetic marketed [36 ],drugs anticonvulsant containing thiazole [37–40 ],rings, etc.). such There as is a largethe anthelmintic number of knowntiabendazole, marketed the antibacterial drugs containing sulfathiazole, thiazole the rings, anticonvulsant such as the riluzole, anthelmintic the tiabendazole,anti-ulcer alizatidine, the antibacterial the antiparkinsonian sulfathiazole, talipexole, the anticonvulsant the antischistosomal riluzole, theniridazole, anti-ulcer the alizatidine,antiviral theritonavir antiparkinsonian and the anti-inflammatory talipexole, the meloxicam. antischistosomal niridazole, the antiviral ritonavir and the anti-inflammatory meloxicam. Molecules 2018, 23, 685 3 of 21 MoleculesThiazolidinones, 2018, 23, x on the other hand, are derivatives of thiazolidine, a saturated form3 of 22 of thiazole,Molecules