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Triazoloquinazoline: Synthetic Strategies and Medicinal Importance

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Tooba Jabeen, Sana Aslam, Matloob Ahmad, Atta ul Haq, Sami A. Al-Hussain and Magdi E.A. Zaki

Submitted: 15 May 2023 Reviewed: 17 May 2023 Published: 13 November 2023

DOI: 10.5772/intechopen.1001898

Recent Advances on Quinazoline IntechOpen
Recent Advances on Quinazoline Edited by Ali Gamal Al-Kaf

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Recent Advances on Quinazoline

Ali Gamal Al-Kaf

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Abstract

Triazoloquinazoline is a fused heterocyclic nucleus, formed by the fusion of two fundamental heterocyclic moieties; triazole and quinazoline. This class of compound is known for its potential as a therapeutic agent and is endowed with several pharmacological applications. Triazoloquinazoline and its derivatives have shown a variety of biological applications such as anticancer, anti-inflammatory, antimicrobial, antiviral, antihypertensive, anticonvulsant, antidiabetic, antioxidant, adenosine receptor antagonist, and significant cytotoxic activities. Hence, this privileged scaffold could act as an important candidate in the field of drug development. Many synthetic protocols have been developed to efficiently synthesize this fused heterocycle and its derivatives. Triazole and quinazoline rings fused at different positions which occurs in various isomeric forms such as, 1,2,4-triazolo[1,5-c]quinazoline, 1,2,4-triazolo[1,5-a]quinazoline, 1,2,4-triazolo[4,3-c]quinazoline, 1,2,4-triazolo[4,3-a]quinazoline, etc. This book chapter covers the synthesis of various isomeric forms of triazoloquinazoline as well as their biological activities.

Keywords

  • Triazoloquinazoline
  • synthesis
  • 1
  • 2
  • 4-triazolo[4
  • 3-c]quinazoline
  • 1
  • 2
  • 4-triazolo[1
  • 5-c]quinazoline
  • triazoloquinazoline derivatives
  • medicinal importance

1. Introduction

Heterocyclic compounds have gained a significant reputation in pharmaceutical chemistry and drug development [1, 2, 3, 4]. Among them, five or six-membered heterocycles containing sulfur and nitrogen atoms have a broad range of biological applications [5, 6, 7]. Triazoloquinazoline is a fundamental fused heterocyclic compound that contains pharmacologically active triazole and quinazoline moieties and possesses a broad bioactivity spectrum. Both heterocyclic moieties have shown considerable interest in the field of medicine and drug development. Quinazoline derivatives have been found to play a substantial role in the development of multitarget agents [8] with a wide range of biological activities such as anticancer [9], anti-inflammatory [10], antimicrobial [11], antihyperlipidemic [12], antihypertensive [13], anticonvulsant [14], antidiabetic [15], cellular phosphorylation inhibition [16], and dihydrofolate reductase inhibition [17]. 1,2,4-Triazole-containing compounds have been reported for pharmacological properties like anticonvulsants, muscle relaxants [18], and anti-histaminic activities [19]. Therefore, the combination of these two active components produce medicinally important scaffold, triazoloquinazoline, which occurs in various isomeric forms such as, 1,2,4-triazolo[1,5-c]quinazoline I, 1,2,4-triazolo[1,5-a]quinazoline II, 1,2,4-triazolo[4,3-c]quinazoline III, 1,2,4-triazolo[4,3-a]quinazoline IV, etc (Figure 1). Many synthetic strategies have been proposed for the facile synthesis of 1,2,4-triazoloquinazoline from 4-hydrazinoquinazoline [20]. 1,2,4-Triazolo[1,5-c]quinazolines have been synthesized by the treatment of 4-hydrazinoquinazolines with aliphatic carboxylic acids [21]. Various substituted 1,2,4-triazoloquinozolines were obtained from hydrazide intermediates [22] and from corresponding thiosemicarbazide derivatives [23, 24]. N-Cyanoimidocarbonates and substituted hydrazinobenzoic acids also act as precursors for the formation of this compound [25, 26]. Various facile synthetic routes such as multicomponent reactions and microwave-assisted synthesis have also been developed (Figure 1) [27, 28, 29, 30].

Figure 1.

Various isomeric forms of triazoloquinazoline.

Triazoloquinazoline constitutes a pharmacologically interesting class of compounds showing a diverse range of biological profiles. This class of compounds and their derivatives have shown prominent biological activities such as anti-hypertonic activity [31], antirheumatic and antianaphylactic activity [21], anti-hypertensive [32], neuro-stimulating activity [21], anti-inflammatory [33], antiviral [34], anti-fungal [35], anti-microbial [35], anti-bacterial [36], anti-oxidant [37], anti-convulsant [38], adenosine receptor antagonists [39], and significant cytotoxic activities [40, 41]. In summary, triazoloquinazoline is an important class of organic compounds that has drawn attention to its potential as a pharmacologically active agent. A number of publications have been made on different synthetic routes as well as medicinal importance of this fused heterocycle.

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2. Synthetic pathways of triazoloquinazolines and derivatives

2.1 Synthesis of [1,2,4]-triazolo[4,3-c]quinazoline

2.1.1 Synthesis from 2-aminobenzoic acid

Many synthetic routes have been developed to efficiently synthesize [1,2,4]-triazolo[4,3-c]quinazolines starting from the commercially available 2-aminobenzoic acid 1. In this regard, Alesawy et al. synthesized derivatives 7a-d, 9a-d, and 10a-d. The compound 1 was reacted with urea 2 at 200°C for 6 h to afford the intermediate 3 which was further treated with phosphorus oxychloride to get 2,4-dichloroquinazoline 4. Then, the dropwise addition of hydrazine hydrate followed by cyclization using triethyl orthoformate yielded compound 6. Compound 6 was further refluxed with various substituted amines to afford 7a-d. The derivatives 9a-d were obtained by reacting compound 8 with aromatic aldehydes using the catalytic amount of glacial acetic acid in ethanol. Finally, the treatment of compound 8 with isothiocyanates in ethanol afforded the derivatives 10a-d [40, 42].

Similarly, Azab et al. in 2022 afforded the derivatives 18a-n and 19. The intermediate 6 was obtained through a similar reaction pathway and further, it was reacted with methyl 4-aminobenzoate under reflux in acetonitrile to afford compound 16. The targeted compounds were obtained by the treatment of 16 with hydrazine hydrate followed by a reaction with appropriate aldehydes in ethanol [43]. El-Adl et al. reacted intermediate 8 with carbon disulfide in KOH using ethanol to afford derivative 11. The derivatives 13a-c were obtained by treating 12 with various substituted chloroacetates in DMF. Furthermore, the final compound 14 was afforded through a reaction with hydrazine hydrate in ethanol. The acetamide derivative 15 was also obtained via treatment with the corresponding reagent [44].

2.1.2 Synthesis from 2,4-dichloroquinazoline

The intermediate 2,4-dichloroquinazoline 4 was used to obtained various [1,2,4]-triazolo[4,3-c]quinazoline derivatives 23(a, b), 25, and 28a-c. The ester derivatives 21a, b were afforded through Fischer Esterification reaction between corresponding benzoic acid using conc. sulfuric acid as a catalyst in the presence of ethanol. These intermediates 21a, b further reacted with hydrazine hydrate to afford compounds 22a, b followed by cyclocondensation with compound 4 in dioxane to obtain derivatives 23a, b. The reaction of compound 4 with hydrazine hydrate afforded compound 5 which was further reacted under different reaction conditions to get derivatives 24, 26a-c. The targeted compound 25 was obtained from the treatment of 24 with POCl3 at 110°C. On the other hand, the derivatives 28a-c were obtained by treating 26a-c with trifluoroacetic acid followed by the reaction with appropriate amines in isopropanol [45, 46].

2.1.3 Synthesis from 4-hydrazinoquinazolines

Many biologically active [1,2,4]-triazolo[4,3-c]quinazoline derivatives have been prepared by the treatment of intermediate 31 with various reagents. The reaction of 4-hydrazinoquinazolines 31 with different substituted aldehydes afforded aryl hydrazones 32 which were further cyclized to form tricyclic compounds 33 in the presence of Br2/AcOH [47]. The condensation of hydrazine derivative 30 with orthoesters produced compound 34 which was modified using a pinacol ester derivative 35 to afford the product 36 [48]. Different researchers employed the intermediate 31 to get various substituted triazoloquinazoline derivatives (37, 38, 39, 40) under different reaction conditions [12, 38, 49, 50, 51].

2.1.4 Synthesis of various substituted triazoloquinazoline derivatives

Ewes et al. synthesized various triazoloquinazoline derivatives from the treatment of dichloroquinazoline 4 with thiosemicarbazide in the presence of n-butanol. The derivative 43 was obtained through the reaction of Schiff bases 42 with aromatic amines in xylene or ethanol. Moreover, the reaction of intermediate 41 with 4-bromobenzenethiol in basic media using acetonitrile afforded amine derivative 44 which was further treated with aromatic acid chlorides to get compound 45. The derivatives 47, 48, 49, and 50 were obtained through the treatment of compound 46 with corresponding reagents [52].

2.1.5 Suzuki-Miyaura coupling and one-pot multicomponent approach

Kopotilova et al. prepared the fluorophores 53 through Suzuki-Miyaura coupling reaction between bromophenyl derivatives 51 and boronic acid or pinacol ester derivative [53]. Reddy et al. employed one-pot reaction between compound 57, substituted aldehydes, and thioglycolic acid in the presence of ZnCl2 using toluene to get thiazolidinone derivatives 58. The intermediate 57 was obtained through the reaction of compound 56 with thiosemicarbazide using ethanol. The starting compound was anthranilamide which undergoes oxidative cyclocondensation with benzaldehyde to afford 55 which was further refluxed with SOCl2 in the presence of DMF to give intermediate 56 [54]. In 2016, Dhongade-Desai et al. described a multicomponent reaction between substituted quinazolinone 59a-f, hydrazine hydrate, and aromatic aldehydes under catalyst-free and microwave irradiation conditions to get derivatives 62a-f [27].

2.2 Synthesis of [1,2,4]-triazolo[1,5-c]quinazoline

2.2.1 Synthesis from aromatic aldehydes

Gusev et al. synthesized [1,2,4]-triazolo[1,5-c]quinazoline derivatives 67 through the reaction between various aromatic aldehydes and intermediate 66 in the presence of ethanol. Intermediate 66 was obtained by the reaction of nitrile 64 with hydrazide 63 using MeOH/MeONa followed by a reaction with ethane-1,2-diol [55].

2.2.2 Synthesis from anthranilic acid

A series of [1,2,4]-triazolo[1,5-c]quinazoline derivatives 74 were prepared by Alagarsamy et al. through the reaction of compound 73 with different aryl amines. Anthranilic acid was used as a starting material and a further simple synthetic pathway leads to the formation of intermediate 73 [56].

Kovalenko et al. synthesized a library of novel anti-cancer agents 77,79 in 53–100% yields following two reaction methodologies. Firstly, the reaction of 4-chloroquinozoline 75 with acid hydrazide afforded the targeted products in reasonable yields. Secondly, the acylation of 76 through the treatment with carboxylic acids using N, N-carbonyldiimidazole in the presence of dioxane. The hydrazone derivatives 78 were obtained through the reaction of compound 76 with aromatic aldehyde in the presence of 2-propanol or dioxane [57].

Martynenko et al. employed the heterocyclization of (3H-Quinazoline-4-ylidene)hydrazides of N-protected amino acids through refluxing in the presence of acetic acid for 3 h. The targeted compounds were obtained by using 4-hydrazinoquinazoline 83 as a starting material. The products were obtained in moderate to high yields (41.2–82.1%) [22].

2.2.3 Synthesis of thio derivatives of [1,2,4]-triazolo[1,5-c]quinazoline

Thio derivatives of [1,2,4]-triazolo[1,5-c]quinazoline 91–95 were synthesized in moderate to high yields through the reaction of intermediate 90 with various reagents. The intermediate 90 was obtained by the treatment of quinazoline-4(3H)-one 87 with Lawesson’s reagent in the presence of dioxane followed by refluxing with hydrazine to afford compound 89. The next step was the cyclization of 89 with potassium ethyl xanthogenate in i-PrOH to form targeted intermediate 90 [58, 59]. Kovalenko et al. elaborated the one-pot synthetic protocol for the synthesis of novel 1-substituted-5-thioxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-1-ium-2-thiolates 98 by the reaction of compound 96 with thiosemicardazide followed by a base-catalyzed reaction of intermediate 97 in the presence of i-PrOH [60].

2.2.4 Synthesis of [1,2,4]triazolo[1,5-c]quinazolines based heterocyclic compounds

[1,2,4]Triazolo[1,5-c] quinazoline-based heterocyclic compounds 102, 103 were prepared by Burbiel et al. The first step involves the reaction of 2-aminobenzonitrile 99 with acyl halides in the presence of chloroform using pyridine as a base followed by the reaction with hydrazine hydrate under microwave irradiations. The resulting compound 100 was treated with nitrile derivative 101 to afford the final compounds [39]. Zeydi et al. refluxed compound 106 with aromatic nitriles using potassium tert-butoxide to get compound 109 [61]. Synthesis of spirocompounds with [1,2,4]triazolo[1,5-c]quinazoline moieties was elaborated by Kholodnyak et al. in 2016 by treating the intermediate 110 with cycloalkanones and diones to afford final products 111 and 112, respectively [62].

2.3 Synthesis of [1,2,4]-triazolo[1,5-a]quinazoline

2.3.1 Synthesis from dialkyl/phenyl N-cyanoimidocarbonates

Different researchers reported the formation of [1,2,4]-triazolo[1,5-a]quinazoline 118 through the coupling of dialkyl/phenyl N-cyanoimidocarbonates or dialkyl/phenyl N-cyanoimidodithiocarbonate 116 with the substituted 2-hydrazinobenzoic acids 117 using triethylamine as a base in the presence of ethanol. The compound 118 was further reacted with several reagents to get derivatives 119, 120, 121, and 122 in moderate to excellent yields [11, 25, 26, 32, 35].

2.3.2 Reaction between cyclohexane-1,3-dione, (DMF-DMA) and aminotriazole

Reaction of cyclohexane-1,3-dione 123 with dimethoxy-N, N-dimethylmethanemine (DMF–DMA), and aminotriazole 125 afforded triazoloquinazoline 126 in high yields. The compound 127 was obtained by the reaction of 126 with NBS and further reaction of compound 127 using potassium carbonate in ethanol produced the dehydrohalogenated product 128. The final derivative 129 was resulted from the treatment of compound 128 with various alkyl halides in DMF using K2CO3 as a base [63].

2.3.3 Schiff base as an intermediate

Schiff base 132 was used as an intermediate for the facile and efficient synthesis of compound 134. The prepared Schiff base was coupled with cyclohexanone in ZnCl2 using glacial acetic acid to afford the targeted product [64].

2.3.4 Synthetic route through diazotization reaction

Diazotization of compound 135 afforded azide 137 which was reacted with arylsulfonylacetonitriles in ethanol to get intermediate 138. The derivatives 139, 140, 141, and 142 were obtained by the treatment of 138 with various reagents [65].

2.3.5 Copper-catalyzed synthesis

Nandwana et al. developed one-pot copper-catalyzed synthetic protocol for the formation of [1,2,4]-triazolo[1,5-a]quinazoline in excellent yield. The reactants for this synthesis were 2-(2-bromoaryl)imidazoles/2-(2-bromoaryl)benzimidazoles 143, alkynes 144, and sodium azide 145 which reacted in the presence of copper catalyst using K2CO3 at 130°C [66].

2.3.6 Reaction between pyrimidine derivative and chalcone

The reaction of pyrimidine derivative 149 with chalcone 148 in the presence of methanol using sodium methoxide at 40–50°C afforded a mixture of products 150 and 151 which were separated by crystallization using propan-2-ol. The starting material 149 was obtained from the reaction between 3-aminotriazole 147 and 1-phenylbut-2-en-1-one 148 [67].

2.4 Synthesis of [1,2,4]-triazolo[3,4-b]quinazoline

2.4.1 Synthesis through two-step reaction

[1,2,4]-Triazolo[3,4-b]quinazoline derivative 161 was synthesized by Xue et al. through a two-step reaction. The first step involves the reaction between isoflavone 158 and 3-amino-1,2,4-triazole 159 in the presence of t-BuOK under microwave irradiations to get intermediate 160. In the second step, this intermediate was undergone photocyclization to afford final derivative 161 in moderate yields [30].

2.5 Synthesis of [1,2,4]-triazolo[3,4-a]quinazoline

2.5.1 Synthesis of diarylidene derivative

Almutaleb et al. reported the synthesis of derivatives 165 by the coupling of aromatic aldehydes 162 with active methylene 133 in the presence of alcoholic KOH to afford intermediate 163 which was further interacted with compound 164 under basic conditions to afford diarylidene derivatives 165 [68].

2.6 Synthesis of [1,2,3]-triazolo[1,5-c]quinazoline

2.6.1 The use of a nanocatalyst for facile synthesis

A Nanocatalyst named Fe3O4@poly(m-phenylenediamine)-@Cu2O was employed by Rawat et al. for the efficient synthesis of [1,2,3]-triazolo[1,5-c]quinazoline derivative 169 from (E)-1-bromo2-(2-nitrovinyl)benzenes 166, aldehydes 167, and sodium azide 168 under mild reaction conditions. The optimized reaction conditions were the use of ethylene glycol as solvent at 100°C for 2 hours [69].

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3. Medicinally important triazoloquinazoline derivatives

Triazoloquinazoline and its derivatives have been reported for various biological applications. Structures of some potent derivatives and their biological activities are described in Table 1.

Table 1.

Structures and biological activities of triazoloquinazoline derivatives.

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4. Conclusion

Since triazoloquinazoline and its derivatives are known for several pharmacological applications, a number of synthetic methodologies have been established for the synthesis of this compound. Some of the most commonly used approaches include; conventional condensation reaction between quinazoline and azide or nitrile, synthesis from chloroquinazoline, copper-catalyzed alkyn-azide cycloaddition reaction, microwave-assisted synthesis, and multicomponent reactions. Moreover, various other simple and efficient synthetic routes have also been reported from time to time. This book chapter compiles the synthetic strategies as well as biological applications of different triazoloquinazoline derivatives published in the past years (2006–2023). This chapter will be very helpful for the researchers working in the field of medicinal chemistry and it would help them to synthesis new triazoloquinazoline derivatives with excellent biological profile.

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Acknowledgments

The authors acknowledge Government College University Faisalabad for support.

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Conflict of interest

The authors declare no conflict of interest.

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Written By

Tooba Jabeen, Sana Aslam, Matloob Ahmad, Atta ul Haq, Sami A. Al-Hussain and Magdi E.A. Zaki

Submitted: 15 May 2023 Reviewed: 17 May 2023 Published: 13 November 2023

© The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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