A Comprehensive Review in Development of Thiazolo[5,4-d]pyrimidines Based Molecules in Medicinal Chemistry 

Review Article

A Comprehensive Review in Development of Thiazolo[5,4-d]pyrimidines Based Molecules in Medicinal Chemistry 

Corresponding author:  Dr. Hesham Fahmy, Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD-57007, USA, Tel: +1 (605) 688-4243 (office);
E-mail: Hesham.Fahmy@sdstate.edu
Thiazolo[5,4-d]pyrimidines are important fused heterocyclic ring-systems which can be considered as purine bioisosteres by virtue of replacement of the nitrogen at position 9 of the purine ring with a sulfur atom. Because of this structural resemblance to purine, there is also structural similarity with adenine and guanine and their related derivatives such as adenosine, guanosine, cAMP, cGMP and other similarly-related biomolecules. Many thiazolo[5,4-d]pyrimidine scaffolds were developed in medicinal chemistry research as potential novel therapeutic agents for many diseases and disorders. Thiazolo[5,4-d]pyrimidines displayed diverse range of pharmacological properties and this review article describes the structural and medicinal significance of all reported thiazolo[5,4-d]pyrimidines in literature up to date. It describes the development of thiazolo[5,4-d]pyrimidines as immunosuppressive agents for treatment of autoimmune diseases and prevention of transplant rejection, phosphatidylinositide 3-kinases (PI3K) inhibitors, Tie-2 inhibitors, RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors, anticancer agents, purine antimetabolites, TRPV1 antagonist for the treatment of pain, thrombin inhibitor, purine nucleoside phosphorylase (PNP) inhibitors, agrochemicals, xanthine oxidase inhibitors and adenosine receptor antagonists.
Keywords: Thiazolo[5,4-d]Pyrimidines; Anti-inflammatory; Antimicrobials; PI3K inhibitor; Thrombin Inhibitors; Fluorescence
List of Abbreviations

PNP: Purine Nucleoside Phosphorylase;
VEGF: Vascular Endothelial cell Growth Factor;
SAR: Structural Activity Relationship;
MAPK: Mitogen-Activated Protein Kinase;
PARP-1: Poly(ADPribose) Polymerase-1;
AR’s: Adenosine Receptors;
TRPV: Transient Receptor Potential Vanilloid type channels;
PI3K: Phosphatidylinositide 3-Kinases;
PIP2: Phosphatidylinositide-4,5-biphosphate;
CHO: Chinese Hamster Ovary

Thiazolo[5,4-d]pyrimidines are bioisosteric heterocyclic compounds of purine bases possessing diverse range of pharmacological activities. They share structural similarity with purine bases related compounds such as hypoxanthine, xanthine, theobromine, caffeine, uric acid as shown in 1. The nitrogen at position 9 of purine is replaced by the sulfur in thiazolo[ 5,4-d]pyrimidines. Thiazolo[5,4-d]pyrimidines , being bioisoteric with purines, have been the subject of intensive studies in medicinal chemistry. They have been explored as pharmacologically active compounds or possible treatments to combat various ailments. Thiazolo[5,4-d] pyrimidines are reported to act as immunosuppressive agents for treatment of autoimmune diseases and prevention of transplant rejection [1, 2], phosphatidylinositide 3-kinases (PI3K) inhibitors [3- 7], agrochemicals and pesticides [8, 9], Tie-2 inhibitors [10], bronchodilators for asthma [11], RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors [12], anticancer agents [13], TRPV1 antagonist for the treatment of pain [14- 16], thrombin inhibitor [17], xanthine oxidase (XOD) inhibitors [18], purine nucleoside phosphorylase (PNP) inhibitors [2]. Furthermore, the fact that they have been explored as purine antimetabolites and hence as anticancer agents has been previously recognized [19].

Figure 1. Structural similarity between thiazolo[5,4-d]pyrimidine and purine and its related compounds.

Structural isomers of thiazolo[5,4-d]pyrimidines

The general structure, numbering system as well as the different isoforms of thiazolo[5-4-d]pyrimidines are shown in Figure 2.

Figure 2. Structural isomers of thiazolo[5,4-d]pyrimidines.

Pharmacological and biological effects of various classes of thiazolo[5,4-d]pyrimidines

Purine nucleoside phosphorylase (PNP) inhibitors

The enzyme purine nucleoside phosphorylase (PNP) catalyzes the phosphorylation of nucleosides to their respective bases, and also catalyzes the reverse reaction which is the conversion of bases to nucleosides. T-cell immunedeficiency leading to autoimmune diseases is often associated with PNP genetic modification. Since proliferating T-cells as implicated in diseases such as rheumatoid arthritis and T-cell leukemia as well as in transplant rejection, PNP inhibitors are explored as potential treatment options for these conditions. Furthermore, PNP inhibitors also showed a potential in treatment of malignant lymphoproliferative diseases [20-23]. A novel thio-isostere (6) of 8-Aminoguanine (5a), and 8-aminoguansoine (5b), was developed as a potential PNP inhibitor(Figure 3) as reported by Sircar et al. [2]. PNP inhibitory activity using [3H]thymidine uptake assay and also the toxicity using T-Lymphoblastoid cell lines were measured. Compound 6 displayed IC50% value of 142.5 μM compared to 1.55 μM and 1.33 μM for the 2-aminoguanines 5a and 5b, respectively. Thus, it was found to be a weaker inhibitor of PNP, however, compound 6 was nontoxic to T-cells under experimental conditions.

Figure 3. Structures of purine nucleoside phosphorylase inhibitor thiazolo[5,4-d]pyrimidines 5a-b and 6.

Thiazolo[5,4-d]pyrimidines as Anticancer agents

Thiazolo[5,4-d]pyrimidines as Tie-2 inhibitors

Angiogenesis inhibition is one of the most widely used targets to develop medicines to treat cancers. The growth andexpansion of the tumors depends on the blood supply and thus inhibition of the angiogenesis is one of the most promisingapproaches to block vascular network and thereby tumors growth [24]. The endothelial cell growth factor (VEGF) is a potentstimulant of angiogenesis and the drug bevacizumab has been shown to bind to VEGF and inhibits angiogenesis [25]. Tie-2 is one of the emerging kinases that stabilizes the immature endothelial network thus promoting angiogenesis. It has attracted the attention of tumor drug development community in recent years [26]. Novel series of imidazole vinyl pyrimidines were developed as potent Tie-2 inhibitors as reported by Butter et al. [27]. However, these compounds suffered from poor photo-stability and also were susceptible to reaction with glutathione leading to undesirable effects. In an effort to prepare more stable and potent molecules, a novel series of thiazolo[ 5,4-d]pyrimidines (Figure 4) were developed as Tie-2/ endothelium-specific receptor tyrosine kinase inhibitors with potential antitumor properties as reported by Luke et al [10]. Structural activity relationship (SAR) studies have shown that the small substituents (methyl or ethyl) on the N1-imidazole ring as in 7a, 7b were associated with decreased potency. However, larger cycloalkyl groups as in compounds 7c, 7d, 7e and 7f showed enhanced potency. Interestingly, compound 7f, with the largest substituents on that position, completely reversed Ang-1 induced hypotension but not VEGF induced hypotension.

Figure 4. Structures of Tie-2 inhibitor thiazolo[5,4-d]pyrimidines 7a-f.

Thiazolo[5,4-d]pyrimidines as Vascular Endothelial

Growth Factor (VEGF) receptor-2 inhibitors

RAF proto-oncogene serine/threonine-protein kinase which is also known as proto-oncogene c-RAF (c-Raf or Raf-1) is anenzyme that is encoded by the RAF1 gene in humans. The c-Raf protein is part of the ERK1/2 pathwayas a Mitogen ActivatedProtein (MAPK) that functions downstream of the Ras sub-family of membrane associated GTP’ases. C-Raf is a member of theRaf kinase family of serine/threonine-specific protein kinases, from the TKL (Tyrosine-kinase-like) group of kinases.

Raf family are important molecules that transduce the mitogen- activated protein kinase (MAPK) pathway signaling and play a major role in diseases associated with the cellular proliferation, differentiation, and survival [28]. Their mutations are often associated with abnormal cancer proliferation. The vascular endothelial growth factor (VEGF) plays an important role in angiogenesis providing support for tumor progression, thus its inhibitors could be of potential value as anticancer treatments.A series of thiazolo[5,4-b]pyridines as highly potent RAF/VEGFR2 inhibitors was earlier reported by Okaniwa et al. [29]. Although, one of the compound had excellent activity, it suffered from poor pharmacokinetics and low thermodynamicsolubility. In an effort to overcome these drawbacks, a novel series of 5-amino-linked thiazolo[5,4-d]pyrimidine derivatives(Figure 5) targeting Raf and VEGF receptor 2 was reported by Hirose et al. [12]. Structural activity relationship (SAR) indicatedthat moderate Raf inhibitory activity (IC50 = 51 nM) and weak cellular pMEK inhibitory activity (IC50 ˃500 nM) were observed for the cyanoethyl derivative 8a. Interestingly, the introduction of dimethyl group to the cyanoethyl functionality in 8b showed a significant increase in cellular pMEK inhibitory activity (IC50 = 150 nM), but with reduction of Raf inhibitory activity. It was also found that introduction of anoxygen atom, as in compound 8c further increased cellular activity (IC50 = 88 nM) along with an increase in Raf inhibition.

Figure 5. Structures of VEGF-2 receptor inhibitor thiazolo[5,4-d]pyrimidines 8a-d.

Another series of novel thiazolo[5,4-d]pyrimidines (Figure 6) with antiproliferative and apoptosis-inducing activity was reportedby Singh et al. [30]. A panel of cancer cell lines such as lung (NCI-H322 and A549), epidermal (A431), glioblastoma (T98G), pancreatic (MIAPaCa-2), prostate (PC-3), human leukemia (HL-60) and breast (T47D) were used to determine apoptosis-induction activity of compounds 9a-f and 10a-n at a single concentration of 10 μM. Significant activity was observed by compound 10k in four cell lines NCIH322, A549, A431 and T98G with 57, 81, 82 and 74% growth inhibition, respectively at 10 mM. Other derivatives also displayed significant growth inhibition in few cell lines and among them was morpholine-substituted analog 10a with 38, 45 and 59% growth inhibition in A549, PC-3 and HL-60 cells, respectively.

The diethylamino-substituted thiazolo[5,4-d]pyrimidine 10K was the most potent among the series with growth inhibitoryeffect of 82, 81 and 74% against A549, A431 and T98G, respectively. Further, apoptotic-induction potential of 10a and 10k by cell cycle and western-blot analysis in HL-60 and A549 cell lines have shown an increase in percentage of apoptotic cells in aconcentration dependent manner from negative 7% (control cells) to 22, 44 and 53% with 1, 3 and 10 mM of 10k, respectively. Also, apoptosis-induction by compounds 10a and 10k was studied by western blot analysis using poly(ADPribose)polymerase-1 (PARP-1) and procaspase-3. PARP-1 is an enzyme essential for the synthesis of poly(ADP-ribose) which in turn is responsible for cell processes including DNA repair and apoptosis.

Figure 6. Structures of antiproliferative thiazolo[5,4-d]pyrimidines 9a-f and 10a-n.

Thus, cleavage of PARP-1[31] promotes apoptosis by preventing DNA repair-induced survival. Procaspase-3 [32] are oftenelevated in the cancer cells and its inhibition proved to be beneficial in cancer treatment. Compound 10a and 10k treatmentshowed clear cleavage of PARP-1 and inhibition of procaspase- 3 in a dose-dependent manner suggesting that both the compounds 10a and 10k induces apoptosis.

Several pyrimidines substituted with trifluoromethyl moieties were synthesized as potential antimetabolites as reported byNagano et al. Structural modification of these compounds lead to development of another novel series of the correspondingtrifluoromethyl-substituted thiazolo[5,4-d]pyrimidines 11a-c (Figure 7) [33]. However, these compounds were found to beinactive as anticancer agents.

Figure 7. Structures of anticancer thiazolo[5,4-d]pyrimidines 11a-c.

Thiazolo[5,4-d]pyrimidines as purine antagonists A series of substituted purines and their corresponding thiazolo[ 5,4-d]pyrimidines were synthesized as purine antagonists aiming at the development of anticancer agents was reported by Robins et al. [34]. Out of the several compounds, derivative 12 (Figure 8) was found to be weakly active.

Figure 8. Structure of purine antagonist thiazolo[5,4-d]pyrimidine 12.

Thiazolo[5,4-d]pyrimidines with miscellaneous anticancer activities

A novel series of thiazolo[5,4-d]pyrimidines 13a-f (Figure 9) with anticancer and antimicrobial activity was reported by sugiura et al. [35]. Anticancer screening of the derivatives in human epidermal carcinoma (HEP3 and FL74), hyernephroma (HN) and mouse sarcoma (S180) showed a weak anticancer activity for all derivatives.

Figure 9. Structures of anticancer and antimicrobial thiazolo[5,4-d] pyrimidines 13a-f.

Thiazolo[5,4-d]pyrimidines as Antimicrobial agents

A novel substituted 2-alkyamino-alkylthiothiazolo[5,4-d]pyrimidines with antimicrobial properties 14a-o (Figure 10) wasreported by Sugiura et al. [35]. The antimicrobial activity of these compounds was assessed against Mycobacterium tuberculosis (H37RV), Streptococcus pyogenes (C203), Staphylococcus aureus (UC 76), Vibrio cholerae (Inaba type), Vibrio cholerae (ogawa type) using isonicotinic acid hydrazide, chloramphenicol and dihydrostreptomycin as standards indicated moderate antimicrobial activity. Further structural modification led to the development of another novel series of thiazolo[5,4-d] pyrimidines 15a-m (Figure 11) with antimicrobial activity was reported by Sugiura et al. [35] with mild to moderate antimicrobial properties.

Figure 10. Structures of antimicrobial thiazolo[5,4-d]pyrimidines 14a-o.

The observation that phleomycin when combined with certain purines showed enhanced activity against Escherichia coli andtheir potential use for the treatment of kidney or urinary tract infections was noticed by Brown and Grigg et al. [36, 37]. Although, the study was encouraging, the oxidative metabolism of the thiolalkyl group of the purines used resulted in loss ofactivity. In an effort to overcome this drawback and the metabolic inactivation en route to target site, a novel series of carbamoyl- containing thiazolo[5,4-d]pyrimidines 16a-t (Figure 12) developed as phleomycin amplifiers was evaluated andreported by Brown et al. [38].

Figure 11. Structures of antimicrobial thiazolo[5,4-d]pyrimidines 15a-m.

All the derivatives were screened as potentiators of phleomycin against E.coli. The most active compounds (16e, 16i, 16l and 16p) had carbamoyl groups which may be due to the resistance of metabolic inactivation. A significant 600-700 fold decreasein viable cell count within 2 hr treatment was observed for compound 16e and 16p at 2 μM and 8 μM, respectively.

Figure 12. Structures of phleomycin amplifier thiazolo[5,4-d]pyrimidines 16a-t.

Encouraged by the findings that many thiazolopyrimidines possess antimicrobial activity, another novel series of thiazolo[5,4-d]pyrimidines 17a-b, 18a-g, 19 and 20a-b (Figure 13) having antimicrobial activity was reported by Basyouni et al. [39]. The synthesized compounds were screened for antimicrobial activity against Bacillus subtilis, S. aureus, E. coli, Pseudomonas aeruginosa, Candida albicans, Aspergillus niger by disk diffusion method using a single concentration of 200 μg/disk. Serial dilution technique was used to calculate minimum inhibitory activity. Compounds 17b, 18b, 18d, 20a and 20b showed activity against B. subtilis. Furthermore, antimicrobial activity against S. aureus and E. coli was observed for compounds 18d and 17b respectively and all other compounds showed weak antimicrobial activity. Further, compounds 17b and 20a showed minimum inhibitory concentration of 100 μg/ ml respectively against all organisms.

Figure 13. Structures of antimicrobial thiazolo[5,4-d]pyrimidines 17a-b, 18a-g, 19 and 20a-b.

In another study, a novel series of thiazolopyrimidines carrying thiosemicarbazide and 1,3-thiazolidin-4-one moieties 22aq(Figure 14) with potent antimicrobial activity was reported by Khairy et al. [40]. Antimicrobial activity against B. subtilis, S.aureus, E. coli, P. auruginosa, C. albicans, A. niger was evaluated using the disk diffusion method using a single concentration of 200 μg/disk. Minimum inhibitory concentration (MIC) study was also carried out using serial dilution technique. High activityagainst B. subtilis was observed for compounds 22h and 22i, and moderate activity against S. aureus by compound 22h.Moreover, good activity towards E. coli, C. albicans, A. niger and weak activity against S. aureus and P. aeruginosa was observed for compound 22i.

Some novel thiazolo[5,4-d]pyrimidines 23a-j (Figure 15) was synthesized by Biginelli condensation reaction as reported byVaghasia et al. [41]. Antimicrobial activity screening was carried out using the cup-plate method against organisms Streptococcus pyogenes (MTCC-442), Streptococcus aureus (MTCC-96) and B. subtilis ( MTCC-441). Fungal activity was carried out using C. albicans (MTCC-227) and A. niger (MTCC-282) organisms. Furthermore, comparison with known standard drugssuch as ampicillin, chloramphenicol, ciprofloxacin, norfloxacin and griseofulvin was also reported. All compounds found to have weak antimicrobial activity compared to the standard drugs.

Thiazolo[5,4-d]pyrimidines as Molluscicidal agents

Schistosomiasis (snail fever) is a parasitic infection caused by parasitic flatworms (schistosomes) affecting roughly 200 millionpeople. It is one of the most important parasitic disease after malaria [42]. The use of molluscicides, thus by interrupting the life cycle of schcistosomes is the most widely used method to eradicate snail [43]. In connection with the previous research on purine analogs, a new series of thiazolo[5,4-d]pyrimidines 24a-J (Figure 16) as molluscicidal agents was reported by Bayouki et al. [44, 45]. All the synthesized compounds were screened for molluscicidal activity against Biomphalaria alexandrina snail. Most of the derivatives showed molluscicidal activity and 100% mortality of snails at 50 and 25 ppm was observed for derivatives 24e and 24j, respectively with 24j as the most potent derivative.

Figure 14. Structures of antimicrobial thiazolo[5,4-d]pyrimidines 22a-q.

Figure 15. Structures of antimicrobial thiazolo[5,4-d]pyrimidines 23a-j.

Figure 16. Structures of molluscicidal thiazolo[5,4-d]pyrimidines24a-j.

Thiazolo[5,4-d] pyrimidines with Fluorescence properties

The use of fluorescent molecules has always played a pivotal rolesin biological and medical research. Among their myriad of uses, fluorescent molecules are usually employed to detect protein location and activation, identify protein complex formation or conformational changes and monitor biological processes both in vitro and in vivo. A novel series of thiazolo[ 5,4-d]pyrimidines 25a-c (Figure 17) with fluorescence properties was reported by Abdullah et al. [46]. Quinine sulfate was considered as a standard for the measurement of fluorescence properties. It was found that the purines derivatives 26a and 26b were more fluorescent than the corresponding thiazolo[5,4-d]pyrimidines counterparts, however the thiazolo[ 5,4-d]pyrimidines were found to have fluorescence maximum at a higher wavelength compared to that of purine derivatives. The observed effect of bathochromic shift in absorption as well as fluorescence shift could be due to the replacement of the carbon atom by heavier atom such as sulfur. Furthermore, the higher fluorescent activity of 5-phenoxythiazolo[5,4-d] pyrimidines than the 2-piperidino derivatives could be attributed to the combined contribution of both the phenoxy and the thiazolopyrimidine rings in the fluorescence than the thiazolo[5,4-d]pyrimidine ring alone in the case of piperidino derivatives.

Figure 17. Structures of fluorescent thiazolo[5,4-d]pyrimidines 25ac and 26a-b.

Thiazolo[5,4-d]pyrimidines as Thrombin inhibitors

Thrombin plays a pivotal role in blood coagulation by activating fibrin formation and stimulating platelet aggregation. Thus,thrombin inhibitors have a potential value in treatment of coagulation related disorders such as arterial and venous thrombosis,deep vein thrombosis, and thromboembolism[47].

Several potent arginine-based thrombin inhibitors such as compounds 27 and 28 (Figure 18) were previously reported by Okamoto et al. [48, 49]. However, high pKa of those molecules had several drawbacks such as short duration of action and poor oral bioavailability.

Figure 18. Structures of thrombin inhibitor thiazolo[5,4-d]pyrimidines 27-29.

Thus, in order to overcome the detrimental properties associated with the arginine group and to develop molecules with ideal properties for oral delivery, a number of arginine surrogates were developed and studied by Baettig et al. [17]. Out of several surrogates proposed, thiazolo[5,4-d]pyrimidines such as compound 29 (Figure 18) were reported as potent thrombininhibitors. Although, Ki value (4.57 μM) of compound 29 was encouraging, it was found to be weaker than the other surrogatesused.

Thiazolo[5,4-d]pyrimidines as Adenosine A3 receptor antagonists

Adenosine is a purine nucleoside chemical mediator. It acts through binding to adenosine receptors A1, A3 (G-protein coupled receptors Gi type) or A2A and A2B (G-protein coupled receptors Gs type) to regulate a number of important biologicalprocesses. Modulation of specific adenosine receptors (ARs) is therapeutically important in many disorders in which adenosine is implicated such as cerebral ischemia, asthma, renal failure, CNS disorders, inflammatory and neurodegenerative diseases [50-53]. Particularly, A3AR has been found to be an attractive target for novel anti-inflammatory drugs as well as for the treatment of glaucoma and in cancer chemotherapy. During development of adenosine receptor (AR) antagonists from different heterocyclic classes, a novel series of 5-methyl-thiazolo[5,4-d]pyrimidine-7-ones 30a-30z and 31a-e (Figure 19) were identified as potent AR antagonists as reported by Varano et al. [54]. All compounds were evaluated for their affinity to hA1, hA2A and hA3ARs stably expressed in CHO cells using radio ligands [3H]DPCPX, [3H]ZM-241385 and [125I]AB-MECA, respectively. Furthermore, inhibition of 5’-(N-ethyl)-carboxamido adenosine (NECA) stimulated adenylyl cyclase activity by these compounds was used to determine efficacy. It was found that high selectivity and good affinity towards hA3AR was observed for thiazolo[5,4-d]pyrimidines bearing a 7-oxo moiety and aryl group on 2-position. A lipophilic 4-chloro, 4-methoxy or 4-methyl group increased hA3AR affinity as seen in 30d with chloro group (Ki 18 nM) which was 5-fold more potent than parent compound 30a. In contrast, loss of both activity and affinity was observed for hydrophobic 4-trifluoromethyl group as in 30e (Ki 107 nM). Further decrease in hA3AR affinity was observed for hydrophilic 4-hydroxyl or 4-carboxy group as seen in 30g and 30h. Also, high activity was observed for p-substitution than m-substitution as evidenced by comparing 30j (Ki 384 nM) and 30k (Ki 826 nM) with 30b (Ki 38 nM), 30c (Ki 33 nM), 30d (Ki 18 nM).

Recently, a rational computer-aided design approach led to discovery of 7-substituted thiazolo-[5,4-d]pyrimidines (Figure 20) as potent and selective A2A receptor partial agonists [55]. This novel series is among few examples of A2A adenosine receptor agonists whose basic structure does not rely on the adenosine scaffold. Considering the thiazolo[5,4-d]pyrimidine core as a bioisostere of adenine, several substituents (e.g. chloro, dialkylamino, five-membered N-heterocycle, and six-membered N-heterocycle) were initially introduced at C7 in order to establish structure-activity relationship. Interestingly, molecular modeling studies showed that the (S)-2-hydroxymethylene- pyrrolidine could mimic the interactions of agonists’ ribose predicting that this class could have agonistic properties. These findings were confirmed by radio-ligand binding assays at the human adenosine receptors subtypes. The analogues bearing a five membered N-heterocycle at C-7 position (32a-n) showed the highest affinity. Their efficacy was also found to be associated with the presence of the 2- hydroxymethylene moiety. Within this series, compounds 32b and 32l were the most potent adenosine A2AAR partial agonists, with Ki values of 200 and 153 nM, respectively. In addition, 32b displayed promising affinity, selectivity profile, and physicochemical properties.

Figure 19. Structures of adenosine A3 receptor antagonists thiazolo[5,4-d]pyrimidines 30a-30z2 and 31a-e.

Figure 20. Structures of adenosine A2A receptor partial agonists thiazolo[ 5,4-d]pyrimidines 32a-n.

This unique class of A2A partial agonists can be an excellent starting point in the design of novel agents for the treatment ofimportant diseases such as epilepsy, cerebral and cardiac ischemia, thrombosis, and arterial hypertension. Furthermore, thestudy has demonstrated that molecular modeling predictions can utilized as a valuable tool to successfully design novel A2Aadenosine receptor agonists.

Thiazolo[5,4-d]pyrimidines as TRPV1 antagonists

Transient receptor potential vanilloid type channels (TRPVs) are family of ion channels [56, 57]. TRPV1 is expressed in airwaysand lungs. Upon stimulation, tachykinins are released resulting in cough, airway irritation and inflammation [58]. TRPVs are also implicated in respiratory diseases. TRPV are stimulated by heat, low pH, capsaicin, endogenous mediators such as bradykinin and anandamide leading to pain signals [59]. Thus, TRPV antagonists have been considered as potential medication for pain [60-62]. In an effort to study structure activity relationship of pyrido[3,4-d]pyrimidines as potent TRPV antagonists, several novel series of thiazolo[5,4-d]pyrimidines 33a-r (Figure 21), 34a-s (Figure 22) and 35a-q (Figure 23) were developed as TRPV antagonists by Lebsack et al. [14] and a potent TRPV antagonist derivative 33a was reported.

N-2-Phenyl modification (Figure 21): Loss of activity was observed when the substituted aniline hydrogen (Compound 33a, IC50 12 nM) was replaced by a methyl group as in compound 33b (IC50502 nM). Generally, 2,6-disubstitution on the phenyl ring resulted in a favorable activity.

Figure 21. Structures of TRPV antagonist thiazolo[5,4-d]pyrimidines 33a-r.

Structure activity relationship studies through N-7-modifications (Figure 22) revealed a substantial loss in TRPV1 potency for derivatives with X = N-CH3 (34a, IC50 > 5000 nM), X = S (34b, IC50 > 5000 nM), and X= O (34c, IC50 > 5000 nM). 4-substitution on the phenyl ring was preferred over 2- and 3-substituted counterparts and potency was maintained with lipophilic functionality such as 4-alkyl analogues as in derivatives 34h-j.

Figure 22. Structures of TRPV antagonist thiazolo[5,4-d]pyrimidines 34a-s.

Structure activity relationship through C5-position modification (Figure 23) revealed an increase in activity when position- 5 was unsubstituted (33a, IC50 = 12 nM) or with methyl substitution (35a, IC50 = 3 nM). On the other hand, phenyl,methylsulfanyl, or methylsulfonyl substitution at C-5 led to loss of activity as evidenced by compounds 35b-d. Also, decrease in potency was observed for tertiary amines groups at the C5-position (35e-h and 35k-m). Increased potency was also observed for secondary amines substitution (35o-p).

Thiazolo[5,4-d]pyrimidines as phospatidylinositide 3-kinase (PI3K) inhibitors

Phosphatidylinositide 3-kinases (PI3K) belong to a family of lipid kinases and play a pivotal role in signal transduction involvedin cell regulation and function. Three classes of PI3Ks have been identified and the class-1 PI3Ks catalyzes the phosphorylationof the 3’-OH group of phosphatidylinositide-4,5-biphosphate (PIP2) to phosphatidylinositide-3,4,5-triphosphate (PIP3).Class-1 has been divided into 1A which contains p110α, β and δ catalytic subunits and 1B with γ subunit [63]. The p110α subunit has been linked to cancer [64, 65]. Insulin receptor tyrosine kinase activates the isoform p110α [66]. The p110β regulates integrin activation and platelet aggregation. Its inhibitors have been shown to prevent arterial thrombosis [67]. Whereas, p110δ and γ subunits have been implicated in immuno deficiency and inflammation [68].

Figure 23. Structures of TRPV antagonist thiazolo[5,4-d]pyrimidines 35a-q.

Some thiazolo[5,4-d]pyrimidines such as compound 36 (Figure 24) is a potent PI3K p110β isoform inhibitor developed to treat arterial thrombosis was reported by Giordanetto et al. [3] at AstraZeneca, using homology model based drug design.

Figure 24. Structure of PI3K inhibitor thiazolo[5,4-d]pyrimidine 36.

Thiazolo [5,4-d] pyrimidines as Immunosuppressive agents

Solid organ transplant is renowned medical treatment and is particularly important in patients with end stage renal, cardiac,hepatic, or pulmonary failure. Successful organ transplant procedure often needs an effective immunosuppression to prevent organ rejection [69]. Currently used immunosuppressive medications include calcineurin inhibitors (cyclosporine A, tacrolimus), antimetabolites (mycophenolatemofetil, azathioprine), mammalian target of rapamycin (mTORa) inhibitors(sirolimus, everolimus), and corticosteroids.

Biosiosteric modification of some previously-reported immunosuppressant pyrido[3,2-d]pyrimidines has led to the developmentof several novel series of thiazolo[5,4-d]pyrimidines 37a-j and 38a-l (Figure 25) as potent immunosuppressive agents was reported by Jang et al [1]. The immunosuppressive activity was evaluated using an allogeneic mixed lymphocyte reaction (MLR) assay and detailed structural activity relationship was studied.

Lack of activity was observed for compounds with aryl groups (37i-j), alkyl group (37h) and sulfonamide groups (37f) even at higher concentrations. Weak activity was observed for the carbamate derivative (37g) and for the unsubstituted compound37a. On the other hand, high potency was observed for the urea and amide derivatives (37d-e, IC50 0.7 and 0.3 μM respectively).

High potency was observed for compounds with a carbon bridge between the 2-position of the thiazolo[5,4-d]pyrimidineheterocyclic core and the 4-fluorphenyl group such as compounds 38a (methyl, IC50 0.7 μM), 38f (propyl, IC50 = 0.92 μM) and 38g (butyl, IC50 = 0.69 μM) compared to compound 36a (IC50 = 4.3 μM) where the 4-fluorophenyl ring is attacheddirectly to position-2.

Figure 25. Structures of immunosuppressive thiazolo[5,4-d]pyrimidines 37a-j and 38a-l.

More derivatives of the thiazolo[5,4-d]pyrimidine (Figure 26) were synthesized and evaluated for their immunosuppressiveproperties [1]. Good immunosuppressive activity was observed for the para fluoro, bromo and methoxy analogues (39b-d, IC50 = 4.38, 3.54 and 3.54 μM, respectively). Whereas the unsubstituted analogue (39a , IC50 = 0.7 μM) demonstrated profound immunosuppressive activity. Also, it was observed that having a 3-pyridinyl ring at position 2 of the thiazolo[5,4-d]pyrimidine core and a 4-fluorophenoxy or 4-methoxyphenoxy acetyl side chain on the 7-piperazinyl moiety led to derivatives 39e (IC50 = 0.96 μM) and 39f (IC50 = 0.92 μM) with potent immunosuppressive activity.

Figure 26. Structures of immunosuppressive thiazolo[5,4-d]pyrimidines 39a-f.

A novel series of immunosuppressive compounds based on a thiazolo[5,4-d]pyrimidine scaffold have been designed andsynthesized applying the isosterism concept [70]. Optimum Scaffold decoration pattern afforded potent in vitro immunosuppressive activity in the mixed lymphocyte reaction (MLR) assay, which is well-known as the in vitro model for in vivo rejection after organ transplantation. In order to establish a reliable structure –activity relationship study, a high degree ofmolecular diversity was introduced at position 7. Unsubstituted piperazinyl group (40a), showed reasonable MLR activity (IC50 = 4.3 μM) and functioned as an excellent starting point for further optimization. Accordingly, a series of substituents was introduced (Figure 27). The introduction of alkyl group (40h) or aryl groups (40i and 40j) led to inactive analogues at 10 μM, the highest tested concentration. The piperazinyl group was also derivatized as amides, urea, carbamates, and sulfonamides.The sulfonamide derivative (40f) was devoid of activity at 10μM, and the carbamate derivative (40g) showed similar activity as unsubstituted compound 40a, while potent activity was associated with amides (40d and 40e). Furthermore, the SAR at position 2 has been intensively investigated. Different linkers were introduced between the aromatic p-fluorophenyl ring and the heterocyclic scaffold. No linker (40b) and a methylene (40k), a propyl (40l), and a butyl (40m) linker all show very comparable MLR activity with IC50 ranging from 0.49 to 0.92 μM. In order to further establish the SAR at position 2, the p-fluorophenyl group was replaced by a p-methylphenyl (40n) and a p-chlorophenyl (40e). These two compounds exhibited IC50 values around 300 nM. Furthermore, a number of heterocyclic aromatics were introduced, as exemplified by the synthesis of the three pyridyl analogues 40p-r. The 2-pyridyl analogue 40r is equipotent with the original lead compound 40b, whereas the 3- and 4-pyridyl analogues show a 10-fold increase in MLR activity, yielding IC50 values of 50 and 40 nM, respectively. This is as potent as cyclosporin A (MLR IC50 = 54 nM), a clinically used immunosuppressive drug, which was included as positive control.

Figure 27. Structures of immunosuppressive thiazolo[5,4-d]pyrimidines 40a-r.

Thiazolo[5,4-d]pyrimidines as agrochemicals

Several novel series of Thiazolo[5,4-d]pyrimidines 41 (Figure 28) were developed as agrochemicals and pesticides to controlfungi, insects, mites and animal parasites as reported by Brewster et al. at Dow Agrosciences [8, 9]. These compounds were evaluated against a variety of undesirable fungi which infect useful plant crops. Moderate to excellent activity has beendemonstrated by these compounds against a variety of fungi, including Downy Mildew of Cucumber (Pseudoperonosporacubensis-PSPECU), Rice Blast (Pyricularia oryzae PYRIOR), Brown Rust of Wheat (Pucciniare conditatritici-PUCCRT) andSeptoria Blotch of Wheat (Septoria tritici-SEPTTR).

Figure 28. Structure of agrochemical Thiazolo[5,4-d]pyrimidines 41.

Thiazolo[5,4-d]pyrimidines as xanthine oxidase inhibitors

Increased uric acid is often associated with gout and renal insufficiency, and with other factors, is implicated in coronarydiseases. Current drugs for hyperuricemia include allopurinol and benzbromalone. These drugs suffer from several side effectssuch as hepatotoxicity and myelogenetic problems. The fact that renal excretion of allopurinol and its oxypurinol metabolite is slowed down with the decrease in uric acid concentrations, poses additional side effects associated with their increased blood concentrations. A novel series of thiazolo[5,4-d] pyrimidines 42 (Figure 29) with xanthine oxidase inhibitory activity was reported by Yoshida et al. as a potential treatment option for gout. The prepared compounds at different concentrations were subjected to an in vitro xanthine oxidase inhibition assay and also in vivo plasma xanthine oxidase inhibition studies using unfasted IRC mouse. Some of the compounds exhibited excellent inhibitory activity with IC50 values ranging from 5.4-119 nM.

Figure 29. Structure of xanthine oxidase inhibitor Thiazolo[5,4-d] pyrimidines 42.

Thiazolo[5,4-d]pyrimidines as adenosine receptor antagonists bronchodilators

Adenosine is an autocoid produced in many tissues and its biological effects are mediated through GPCRs namely A1, A2A, A2B and A3. A1 and A3 receptors belong to GPCRs of Gi and Go type, while A2A and A2B to Gs type [50]. Due to this, adenosineactions through A2A and A2B receptors leads to increase in intracellular cAMP levels and an increase in intracellular Ca2+ ion levels. These A2B receptors has a role in the hepatic glucose production and thus their inhibition have a potential in treating type 2 diabetes. A2B receptors are also present in the plasma membranes of endothelial cells of blood vessels and have been found to stimulate their growth leading to the growth of new blood vessels. Thus, A2B inhibitors have also a potential in treatment of diseases characterized by abnormal blood vessel growth, such as diabetic retinopathy. Furthermore, adenosine A2B receptors are expressed in human airway smooth muscle cells and lung by fibroblast cells and have been linked to inflammation and asthma [51]. Thus A2B inhibitors have a potential in treating asthma. A novel series of thiazolo[5,4-d]pyrimidines 43 (Figure 30), with adenosine A2B receptor inhibitory properties and potential applications in asthma was reported by Brinkman et al. [11].

Figure 30. Structure of adenosine A2B antagonist Thiazolo[5,4-d]pyrimidines bronchodilators 43.
The inhibition of the agonist-induced cyclic AMP production (by 5’-N-ethylcarboxamidoadenosine, NECA) produced by thisseries of compounds was evaluated in Chinese hamster ovary (CHO.K1) cells expressing human adenosine A2B receptor where many compounds showed a good inhibition with IC50 values ranging from 0.002 to 1.56 μM.


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