Introduction

At present, one of the most promising strategies in creating new pharmaceuticals is the design and synthesis of hybrid compounds. These compounds typically consist of two or more different covalently linked bioactive fragments (pharmacophores) and operate via the activation of several mechanisms at single or multiple targets. Single agent therapy is not able to provide effective and long-term control of the malignant process due to the development of drug resistance, insufficient selectivity, and high toxicity (Lavi 2015; Bérubé 2016). Hybrid compounds overcome many of the disadvantages of individual drugs, such as low solubility, side effects, and multidrug resistance, which leads to a more pronounced therapeutic effect compared with individual components. Multipurpose hybrids also have certain advantages in comparison with the combined therapeutic approach such as superior bioavailability, low toxicity, they allow to more accurately predict the pharmacokinetic and pharmacodynamic profile, simpler patient compliance, higher treatment efficacy, and lower treatment costs. Multipurpose hybrids, as a rule, are created by linking the framework of two target selective ligands or pharmacophores with the total therapeutic effect exceeding the action of each individual ligand (Ganesan 2016; Musso et al. 2015; Kerru et al. 2017; Fortin and Bérubé 2013; Nepali et al. 2014).

Molecular modeling allows for the creation of drugs that combine the structural features of selective ligands to produce hybrids with several pharmacophore groups aimed at different types of targets. The most common design of multifunctional hybrids is based on the connection through a spacer of two selected pharmacophores with the ability to bind to different therapeutic targets.

The combination of the quinazoline cycle and hydroxamic acids is one of the unique pharmacophore groups that contributes to widely used medicinal agents in medical chemistry. The simplicity of their preparation and availability of feedstock, as well as the high biological activity of these compounds, has led to the creation of multifunctional hybrid compounds that showed higher efficiency than the individual components or their additive use (Fortin and Bérubé 2013; Nepali et al. 2014; Hesham et al. 2018; Zhang et al. 2014; Schobert and Biersack 2017; Gupta 2013; Muri et al. 2002; Lou and Yang 2003). The creation and implementation of multifunctional preparations in the new generation of practice is actively developing throughout the world as evidenced by many experimental studies published across the world. This review is an attempt to detail and classify the most significant and promising developments based on the hybridization of hydroxamic acids and the quinazoline cycle.

Hydroxamic acid and the quinazoline cycle are important pharmacophore fragments

Hydroxamic acids and the quinazoline cycle are unique pharmacophore groups that are often present in drugs widely used in medical chemistry.

Hydroxamic acids, represented by the general formula RC(O)NR′OH, exhibit a wide spectrum of biological activity. In addition, they are easy to prepare and there is readily accessible feedstock, making them a desirable agent for both practical and research purposes (Gupta 2013).

Due to the ability of hydroxamic acids to form complexes with various metal ions, in particular iron, zinc, magnesium and calcium (the most common metals in metal-containing proteins), they possess a number of unique biological and pharmacological properties. Hydroxamic acids are capable of the inhibition of a variety of enzymes, including matrix metalloprotease, peroxidase, hydrolase, urease, lipoxygenase, cyclooxygenase, histone deacetylase, peptide deformylase (Gupta 2013; Muri et al. 2002; Lou and Yang 2003). In medical chemistry, hydroxamic acids are used in the design of therapeutic agents against hypertension (Zamora et al. 1995), cancer (Manal et al. 2016), malaria (Giannini et al. 2015), tuberculosis (Rao et al. 2018), HIV, Alzheimer’s disease (Rao 1992; Xu et al. 2011), cardiovascular disorders (Yoon and Eom 2016), and others diseases (Qiu et al. 2017). Effective histone deacetylase inhibitors (HDACi) have been found among hydroxamic acid derivatives; in particular, Vorinostat (SAHA), Panobinostat (LBH589) and Belinostat have been approved by the US FDA for the treatment of cutaneous T-cell lymphoma and multiple myeloma (Mottamal et al. 2015) (Fig. 1).

Fig. 1
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Hydroxamic acids registered as HDACi

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It should be noted that although HDAC inhibitors during monotherapy showed moderately high antitumor activity, their combined use with many structurally and functionally diverse drugs and biologically active peptides was more effective (Bolden et al. 2006; Suraweera et al. 2018; Arrighetti et al. 2015). Modern methods of chemical synthesis make it possible to introduce a hydroxamate group into the molecules of various natural and synthetic compounds, including well-known pharmaceutical preparations. For example, derivatives of camptothecin, doxorubicin, and colchicine were synthesized (Fig. 2). These and many other examples are described in comprehensive reviews (Musso et al. 2015; Hesham et al. 2018; Papavassiliou and Papavassiliou 2013; Seo 2012). Such hybridization increases their therapeutic effect. The development of this direction led to the synthesis of new multitarget hybrid compounds.

Fig. 2
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Design of dual-acting hybrids with hydroxamate moiety

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In turn, the quinazoline cycle is also an important pharmacophore fragment. Derivatives of quinazoline and dihydroquinazoline are currently widely used in clinical practice (Khan et al. 2016; Shagufta and Ahmad 2017; Hemalatha and Madhumitha 2016), with preclinical studies of new derivatives at anongoing status. The quinazoline cycle is present both in various natural compounds and in the molecules of more than a hundred drugs. This can be attributed to its diverse activity, including antibacterial, antifungal, anti-inflammatory, antimalarial, antiviral, anti-tuberculosis properties, as well as its inhibitory effect on thymidyl synthase, poly (ADP-ribose) polymerase and tyrosine kinase (Asif 2014) (Fig. 3).

Fig. 3
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Examples of quinazoline drugs

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The combination of these pharmacophores in one molecule can potentially lead to new promising compounds, as evidenced by numerous examples. In this review, we examined the biologically active compounds described in the literature that combine the quinazoline cycle and hydroxamate group in one molecule. Compounds with both linear hydroxamic acids and cyclic acids in which a hydroxamate group is integrated in the quinazoline ring are also covered.

Compounds with hydroxamate function included in the quinazoline cycle

The hydroxamate function in quinazolinones can be included in the heterocyclic ring as an endocyclic N-hydroxy group, forming a cyclic hydroxamic acid (Fig. 4).

Fig. 4
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The structure of compounds with hydroxamate function included in the quinazoline cycle

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One of the advantages of compounds with an endocyclic N-hydroxy group is their high metabolic stability, as it is known that in linear hydroxamic acids, single N–O bonds can be metabolized to highly reactive compounds that cause serious side effects (Rani and Granchi 2015).

Biological activity of cyclic hydroxamic acids

The endocyclic N-hydroxy group is present in a number of natural compounds, for example, in some siderophores (Carboxymycobactin, Heterobactin B, Cepabactin), which function as ligands and carriers of iron ions in bacteria (Hider and Kong 2010). The high affinity of hydroxates for iron ions allows the Fe3+ compounds to be dissolved and transported into the cell, where it is reduced to Fe2+. Compounds of this class are also found in the products of fungal metabolism (Phaeosphaeride A) (Maloney et al. 2006; Abzianidze et al. 2015; Kobayashi et al. 2015) (Fig. 5).

Fig. 5
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Natural biologically active compounds with cyclic hydroxamate function

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One of the most studied natural compounds of this class are the benzaxazinoids, DIBOA, and DIMBOA (2,4-dihydroxy-2H-1,4-benzoxazin-3 (4H) -ones), which are responsible for the resistance of cereal plants to pests and diseases (Fig. 5) (Niemeyer 1988, 2009). In case of damage to plant tissue, these substances are formed in the form of secondary metabolites that have insecticidal and fungicidal effects.

Cyclic hydroxamic acids are a universal class of compounds that form the basis for the creation of many new therapeutic agents. In the last decade, active studies of cyclic hydroxamic acids have been conducted to create a class of antiretroviral drugs for the treatment of HIV-1 infection. A number of experimental studies have shown that clinical inhibitors of HIV-1 integrase (IN) effectively inhibit virus replication with a sharp decrease in viral load. A series of N-hydroxy-dihydronaphthyridinone derivatives (compound 1), specific HIV-1 IN inhibitors with high efficiency and an excellent resistance profile, were designed, synthesized and evaluated (Fig. 4) (Pryde et al. 2013). A biological evaluation of a series of substituted 1,8-dihydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides (compounds 2 and 3) was completed, providing selective inhibition of not only IN but also RNase H, which until recently was the only enzyme clinically unconfirmed as an antiviral target (Zhao et al. 2014). However, the emergence of resistance to these drugs underlines the need to develop next-generation IN catalyst inhibitors with improved resistance profiles. One of the latest developments includes IN inhibitors, and derivatives of 2-hydroxyisoquinoline-1,3(2H,4H)-dione (compound 4), which are potential agents for further preclinical development as a next-generation IN inhibitor (Fig. 6) (Tang et al. 2017; Billamboz et al. 2016).

Fig. 6
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Synthetic biologically active compounds with cyclic hydroxamate function

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A series of arylsulfonamide-based matrix metalloproteinase (MMP) inhibitors (compounds 5 and 6) with a cyclic hydroxamate fragment acting as Zn-binding groups selectively inhibiting MMP-2 and MMP-9 with IC50 values of 10.6 and 16.4 μM, respectively, were synthesized (Fig. 4) (Zhang et al. 2008a, 2008b). Also, HDACi were synthesized as a Zn-binding agent in the class of 5-membered cyclic hydroxamic acids (compound 7). However, these compounds showed low activity against extracts of HeLa cells; therefore, this group requires additional research in order to search and develop more active compounds (Mutule et al. 2014).

The biological activity of cyclic hydroxamic acids included in the quinazoline cycle

Until 2000, experimental studies on hydroxamic acids associated with quinazoline possessing biological activity were lacking. One of the first synthesized compounds with an endocyclic N-hydroxy group included in the quinazoline cycle was described in 1970 by Bonola and Sianesi (1970). The authors of the study synthesized a series of derivatives of 3-hydroxy-2,3-dihydro-4(1H)-quinazolines (compound 8) as potential antibacterial and antifungal agents (Fig. 7). Later, a derivative of 3-hydroxyquinazolin-4-one (compound 9), which exhibited an inhibitory effect on trypanosomal glycerol-3-phosphate oxidase, was reported (Grady et al. 1986). Jung et al. (1985) studied the genotoxicity of furan derivatives of 3-hydroxy-2,3-dihydroquinazolin-4-ones. The nitrofuran derivative (compound 10) was found to be the most active in mutagenicity tests (Fig. 7). Based on the test results, it was found that the carcinogenicity of this compound may be due to the ability to induce mutations in the hereditary apparatus of the cell.

Fig. 7
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Cyclic hydroxamic acids in the quinazoline cycle with potential biological activities

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As a result of the development of molecular modeling in recent decades, the list of pharmaceuticals that include quinazoline derivatives and hydroxamic acid in the molecule has expanded significantly. Compelling progress has been noted in the development of hybrid compounds, which are promising in the complex treatment of infectious and oncological diseases.

Compounds with antibacterial, antiviral, and fungicidal effects

Since the 2000s, a series of works has been executed on the synthesis of antibacterial and fungicidal drugs. During the experiments, 2,2′-disubstituted derivatives of 3-hydroxy-2,3-dihydro-4(1H)-quinazolinone (compound 11) were developed, which are promising fungicides against fungi of various taxonomic classes (Fig. 8) (Kotov et al. 2001). Compounds of this series were also studied for antiglutamatergic activity (Fetisov et al. 1999). As a compound with fungicidal and growth-regulating properties, 3-hydroxy-2-thioxo-4(3H)-quinazolinone (compound 12) was proposed (Khohlov et al. 2005). In continuation of the work, its derivatives were synthesized (Khohlov, Osipov 2011); compound 13 was declared as an antiviral, antibacterial, and fungicidal agent (Khokhlov et al. 2005, 2011).

Fig. 8
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A group of antibacterial, antifungal, and antiviral compounds based on cyclic hydroxamic acids and a quinazoline cycle

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The synthesis of a series of DNA gyrase inhibitors allowed an increase in the class of antibacterial agents. The most active compound from this series (compound 14) showed high intracellular activity (MIC = 0.13–4.0 mg/ml) against laboratory strains of model microorganisms (Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, and Streptococcus pyogenes) which quantitatively corresponds to that for ciprofloxacin, a synthetic antibiotic with a similar pharmaceutical effect (MIC = 0.06–4.0 mg/ml) (Tran et al. 2004). In parallel, other experimental studies synthesized substituted 3-hydroxyquinazolin-4-ones (compound 15) with antimicrobial activity against model microorganisms of the ATCC collection (S. aureus, B. subtilis, E.coli, P. aeruginosa, and S. albicans) (Dikii et al. 2006).

One of the latest and promising antimicrobial developments relates to acetohydroxyacid synthase (AHAS) inhibitors, which are seen as a promising drug target against Mycobacterium tuberculosis (MTB). Using molecular docking followed by a search for similarities, 23 new AHAS inhibitors were found, including derivatives of 3-benzoyloxyquinazinone (Wang et al. 2013). The IC50 values for bacterial AHAS inhibitors for compounds 16 and 17 were 1.85 ± 0.19 and 2.02 ± 0.15 μM, respectively (Fig. 8). In continuation of these studies, 24 additional quinazolinonebenzoates were synthesized and their antituberculous activity was studied (Lu et al. 2015). Compound 18 showed significant inhibition of MTB-AHAS, with an IC50 value of 6.50 μM. It should be noted that this compound also showed in vitro intracellular activity against clinically isolated strains of drug-resistant MTB (MIC = 2.5–10 mg/L). These results showed that quinazolinone benzoate compounds should be considered as promising compounds for the development of effective anti-tuberculosis drugs with a possible new mode of action.

As mentioned above, cyclic hydroxamic acids have gathered strong interest as antiviral agents. One of the first studies was conducted by Bristol-Myers Squibb in 1996. Large-scale bioscreening revealed the active antiviral compounds BMY-183021 (19) and BMY-183355 (20) (Fig. 8), which are cyclic hydroxamic acids with the (3H)-quinazolinone ring, selectively inhibiting the transcriptases of influenza A and B viruses (IC50 = 40–50 μM) (Cianci et al. 1996).

Following these findings, substituted 3-hydroxyquinazolin-4-ones were synthesized that inhibit the hepatitis C virus (HCV) NS5B polymerase (Deore et al. 2012). The optimization of their structure led to the identification of N-phenylpropylcarboxamide (compound 21) (Fig. 8), which displayed activity against HCV NS5B polymerase with IC50 = 8.8 μM. Compound 21 has selectivity for Ava5 cells, HCV1b replicon (EC50 = 17.5 μM) when compared with parent HuH-7 human hepatocarcinoma cells (EC50 = 187.5 μM).

There is particular interest in the class of cyclic hydroxamic acids that is attracted by compounds that are potential antitumor drugs (Fig. 9). In a series of studies, the synthesis of 3-hydroxy-1H-quinazolin-2,4-dione (compound 22) was completed and the activity of these compounds as selective antagonists of the ionotropic glutamate receptors was confirmed, including the Gly/NMDA, AMPA and kainate (KARs) receptors (Colotta et al. 2004; Colotta et al. 2012; Catarzi et al. 2010). Most of the compounds in this series showed high affinity for both AMPA and KARs receptors, as well as for the Gly/NMDA site. The most active compound was 6-(2-carboxybenzoylamino)-3-hydroxy-1H-quinazoline-2,4-dione (compound 23), which not only showed high affinity for high-affinity and low-affinity CA receptors (Ki = 0.62 μM and Ki = 1.6 μM, respectively) but also high selectivity (Colotta et al. 2006). Substances from this class have also been shown to be potential inhibitors of tumor-associated human carbonic anhydrase. (hCAs) IX and XII isoforms (Falsini et al. 2017). 3-hydroxyquinazoline-2,4-diones were identified as inhibitors of flap endonuclease 1 (FEN1) (compound 24) (Tumey et al. 2005). It has been experimentally shown that the compounds of this group are 100 times more effective than known FEN1 inhibitors (IC50 0.014–0.079 μM). Also, more than 1000-fold specificity was achieved in relation to the related endonuclease of pigment xeroderma G, the activity against which was IC50 = 0.16–0.19 μM.

Fig. 9
figure 9

Antineoplastic compounds based on cyclic hydroxamic acids included in the quinazoline cycle

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Some of the considered group of hybrid compounds may be potential agents not only in the treatment of infectious and oncological diseases but also in the complex treatment of neurological pathologies. It was experimentally shown that the synthesized derivatives of quinazolin-4(1H)-one inhibit myeloperoxidase with IC50 values up to 100 nM, including the 3-hydroxyquinazolin-4(3H)-one derivative (compound 25) (Li et al. 2015). Myeloperoxidase is a key antimicrobial enzyme that plays a key role in protecting the host and is able to participate in the development of inflammatory diseases, such as Parkinson’s and Alzheimer’s.

Linear hydroxamic acids linked to the quinazoline cycle

Hydroxamic acid and the quinazoline ring can be covalently connected via various linkers, allowing the molecule to freely interact with different targets. The chemical nature of hydroxamic acid and derivatives of quinazoline enables the creation of a variety of bifunctional molecules by varying the position at which hydroxamic acid is attached to the quinazoline cycle. Most often, hybrid compounds containing hydroxamic acids and the quinazoline cycle are used to increase the effectiveness of chemotherapy as multipurpose antitumor agents, which can be classified into several groups according to the type of action.

Selective MMP inhibitors

Selective MMP inhibitors were one of the first antitumor drugs based on the synthesis of hybrid compounds of hydroxamic acid and the quinazoline cycle. Overexpression of MMPs is involved in various pathological conditions, such as cancer, arthritis, cardiovascular disease, and neurological disorders. In this regard, MMPs are considered therapeutic targets and many MMP inhibitors have been developed over the past two decades, including hybrid compounds of quinazoline and hydroxamic acid. Thus, tumor necrosis factor α-convertase (TACE) is a metalloprotease-disintegrin closely associated with MMPs. Modern TACE inhibitors, such as succinate-based hydroxamic acids, for example Marimastat (TACE IC50 = 3.8 nM; blood IC50 = 7 μM), showed weak activity in vivo and in the blood. To solve this problem, volumetric substituents were introduced into succinate-based hydroxamic acids. The optimization of this series of sulfonamides resulted in the synthesis of heterocyclic bicyclic sulfonamides, of which compound 26 (Fig. 10) was selected for further studies (TACE IC50 = 0.57 nM; blood IC50 = 0.28 μM) (Barlaam et al. 1999). However, none of these compounds has been successfully tested in clinical trials due to insufficient efficacy and long-term dose-limiting side effects in diseases such as cancer and arthritis. Despite these disadvantages, inhibition of MMP is still considered an effective therapeutic approach. In the studied series of new hydroxamic acids, effective and specific inhibitors of MMP-2,3,9,13, one of the compounds is a derivative of 4-quinazolinone (Chollet et al. 2001). Among the latest developments of selective matrix metalloprotease-13 inhibitors (MMP-13), a Zn-linking group was used with the quinazoline-2-carboxamide system. The synthesized compounds 27, 28, 29 (Fig. 10) showed high activity and selectivity to other types of MMP (Nara et al. 2016, 2017).

Fig. 10
figure 10

Selective matrix metalloprotease inhibitors (MMPs)

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HDAC inhibitors

Over the past few years, there has been developments to the synthesis of hydroxamic acid-based HDAC inhibitors with quinazoline fragments, where the latter act as an effective surface interaction domain (“cap”) with active enzyme sites (Fig. 11).

Fig. 11
figure 11

Examples of HDAC inhibitors with a quinazoline cycle as the surface recognition domain of the enzyme site (“cap”)

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The 4-aminoquinazoline derivative (compound 30) significantly inhibited HDAC6 (IC50 = 17 nM) with 25-fold selectivity for HDAC1 and 200-fold selectivity for HDAC8 (Yang et al. 2015). It also inhibited the growth of 11 different hematologic and solid tumor cell lines more efficiently than SAHA, with IC50 in the low nanomolar ranges. It was determined that compound 30 increased the level of acetylation of α-tubulin in vitro. In in vivo experiments, compound 30 more effectively inhibited tumor growth in colorectal cancer (HCT116), acute myelocytic leukemia (MV4-11), and Romas xenograft B cell lymphoma when compared with SAHA, even at a fourfold reduced dose. In addition, it had excellent oral bioavailability in rats (47%).

Based on compound 30, a further 58 more compounds were synthesized (Chen et al. 2018). Among which, compound 31 not only performed as the most potent inhibitor of HDAC1 and HDAC6 (HDAC1, IC50 = 31.10 nM; HDAC6, IC50 = 16.15 nM) double-acting with more than tenfold selectivity for other histone deacetylases (HDACs) but also showed activity against tubulin acetylation and histone H3 acetylation induction. It is important to note that compound 31 had strong antiproliferative activity against various in vitro tumor cell lines with IC50 values of <40 nM, particularly for hematological tumor cells (U266 and RPMI8226, IC50 < 1 nM), which was superior to compound 30 and SAHA. In addition, compound 31 showed significant inhibition of tumor growth in the MCF-7/ADR resistant xenograft model without any apparent changes in body weight or behavior.

Zhang et al. (2017) studied a series of hydroxamic acid-based HDACi with 4-aminoquinazolinyl fragments was studied. Most compounds showed stronger HDAC inhibition activity than SAHA. Some compounds selectively inhibited HDAC1,2 when compared with HDAC8, and exhibited strong activity on several cell lines while not having significant toxicity to primary human cells. The most promising agent was compound 32 (R = 6-Cl, n = 6) (Fig. 11) which had acceptable pharmacokinetic characteristics and showed significant antitumor activity in the study on the A549 xenograft model at well-tolerated doses.

Hieu et al. (2018a) studied hydroxamic acids analogous to compound 32 and new N-hydroxybenzamides, including a 4-aminoquinazolyl fragment (compound 33), were designed and synthesized. Biological evaluation showed that these hydroxamic acids and N-hydroxybenzamides are highly cytotoxic to three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). Regarding cytotoxicity, some compounds showed 5 to 10 times higher efficacy than SAHA. The compounds are also generally comparable with SAHA in HDAC inhibition with IC50 values in the submicromolar range.

The aforementioned authors (Hieu et al. 2018b) also synthesized several series of new N-hydroxybenzamides (compound 34) and N-hydroxypropenamides (compound 35) containing quinazolin-4 (3H)-one. Several compounds showed a fourfold higher cytotoxic activity than SAHA with respect to three human cancer cell lines (SW620, PC-3, and NCI-H23) and inhibited HDAC with IC50 values in the submicromolar range. It has been found that N-hydroxypropenamides (compound 36) are most effective both in terms of HDAC inhibition and cytotoxicity.

As HDAC6 inhibitors, a series of new quinazolin-4-one derivatives containing a conjugated hydroxamic acid fragment was studied (Yu et al. 2013). Most of these derivatives showed selective inhibition of HDAC6 with nanomolar IC50 values, caused neurite growth accompanied by the expression of growth-associated protein 43, and enhanced the synaptic activity of PC12 and SH-SY5Y neuronal cells without causing toxic or mitogenic effects. The most promising drug candidate, compound 36, selectively inhibits HDAC6 with an IC50 of 29 nM, increases α-tubulin acetylation, and reduces the aggregation of zinc-bound β-amyloid in vitro. In addition, this compound significantly improved performance in training mice with β-amyloid-induced hippocampal lesions. Compound 36 may be a good leader in the development of selective HDAC6 inhibitors for the treatment of Alzheimer’s disease.

Multipurpose inhibitors

The discovery of the synergistic effect of the studied pharmacophores on cancer cells made it possible to apply a new method for constructing antitumor drugs (Fig. 12) where their action is based on the simultaneous inhibition of several targets involved in the protection and survival of tumor cells. Hybrid compounds directed at more than one target have proved to be more effective and powerful antitumor agents.

Fig. 12
figure 12

Example strategy for creating multipurpose inhibitors using the binary VEGFR-2/HDAC inhibitor as an example (compound 38)

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Dual inhibitors

Compound 37 and its analogs are patented as dual VEGFR-2/HDAC inhibitors (Fig. 13). However, the biological evaluation discussed in the patent only concerns HDAC inhibition; the question of the inhibition of VEGFR-2 by these compounds remains open (Qian et al. 2009). Later, studies were conducted on several similar hybrid molecules acting on HDAC and other targets. For example, compounds 38 (Fig. 13), including N-phenyl-4-aminoquinazoline and hydroxamic acid in the structure, were synthesized and studied as double VEGFR-2/HDAC inhibitors. The most active compound from this series inhibited HDAC with IC50 = 2.2 nM and VEGFR-2 with IC50 = 74 nM. Moreover, it significantly inhibited the enzymatic activity on lung cancer cells MCF-7 with IC50 = 0.85 μM (Peng et al. 2015; Peng et al. 2016), which is an example that perfectly illustrates the effectiveness of this strategy.

Fig. 13
figure 13

Examples of double inhibitors with a quinazoline cycle in the molecule

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Inhibitors of bromodomain and extra-terminal domain (BET) proteins and HDAC are known to kill cancer cells in murine lymphoma synergistically. The study (Shao et al. 2017) combined the fragments responsible for the inhibitory activity of BET and HDAC into one molecule using the structural design method using known inhibitors. Most synthesized compounds 39 (Fig. 13) showed inhibitory activity against bromdomains (BRD) BRD4 and histone deacetylase HDAC1.

Protein-lysine methyltransferase G9a (PKMT G9a) and HDACs are therapeutic targets for cancer therapy targeting identical substrates (H3K9 and p53 lysine 373). In search of a lead molecule with inhibition of both HDAC and G9a, the quinazoline core of G9a inhibitors was chosen as the main framework. As a result of the synthesis of more than 20 compounds and further investigation of the activity of in vitro, compound 40 was found (Fig. 13) which demonstrated significant inhibition of both G9a and HDAC in the low micromolar range in experiments on cells (Zang et al. 2017).

A series of novel hybrids based on the 3-amino-10-hydroxyl-evodiamine scaffold and SAHA were identified as triple inhibitors of topoisomerase I/II/ HDAC (He et al. 2015). In particular, compound 41 showed excellent antiproliferative activity against MDA-MB breast carcinoma cells (IC50 = 2.3 μM), HCT116 colon carcinoma cells (IC50 = 0.41 μM) and HLF liver cancer cells (IC50 = 1.3 μM), provided good inhibitory activity against HDAC1 (IC50 = 24 nM), HDAC6 (IC50 = 13 nM) and HDAC8 (IC50 = 2.5 nM), and topoisomerase I/II, comparable with standard inhibitors (Camptothecin and Etoposide). This proof-of-concept study also validated the effectiveness of discovering triple topoisomerase I/II and HDAC inhibitors as novel antitumor agents.

EGFR/HER2/HDAC inhibitors

The discovered synergistic effect of inhibition of epidermal growth factor receptor proteins (EGFR), human epidermal growth factor receptors 2 (HER2) and HDAC allowed us to apply a new drug development method (Fig. 14). Based on the Lapatinib EGFR/HER2 inhibitor (Lapatinib), chimeric HDAC inhibitors were obtained (compound 42). In biological trials, these analogs demonstrate selective and significant inhibition of EGFR/HER2, as well as the enzymatic activity of HDAC. In cell tests, using the Cal27 head and neck cell line as an example, a dose-dependent inhibition of EGFR phosphorylation and the induction of histone acetylation are observed (Mahboobi et al. 2010). In continuation of this work, a series of 43 hybrids based on Erlotinib (Erlotinib), inhibiting HDAC, EGFR, and HER2 kinases, was synthesized (Beckers et al. 2012).

Fig. 14
figure 14

EGFR/HER2/HDAC Inhibitors

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Using a similar strategy for combining receptor tyrosine kinase inhibitors and Belinostat HDAC inhibitor, several dual-targeted inhibitors were constructed (Zhang et al. 2013). Among which, compound 44 showed anti-HDAC activity comparable with SAHA, however, the inhibitory effect against EGFR and HER2 was low.

By combining the pharmacophores of the EGFR/HER2 inhibitor Sapitinib (AZD-8931) and Vorinostat into a single compound, a new series of multipurpose inhibitors EGFR, HER2, and HDAC was synthesized (Ding et al. 2017). The compounds contain 4-anilinoquinazolines with C-6 triazole-linked long alkyl chains of hydroxamic acid. Compound 45 showed the highest inhibitory activity against EGFR, HDAC1, and HDAC6 with IC50 values of 0.12, 0.72, and 3.2 nM, respectively. In addition, this compound significantly inhibited the proliferation of five human cancer cell lines: A549, BT-474, HER2-A431, SK-BR-3, and NCI-H1975(IC50 between 0.49 and 8.76 μM). Further studies showed that compound 45 regulated the phosphorylation of EGFR and HER2 and the hyperacetylation of histone H3 at the cellular level and caused apoptosis in BT-474 cells.

The most successful multipurpose antitumor drug was compound CUDC-101 (compound 46), created as an EGFR/HER2/HDAC inhibitor (Wang et al. 2013) (Fig. 14). In in vitro experiments, CUDC-101 effectively inhibits the activity of EGFR and HER2 kinase and HDAC enzymes with IC50 values of 2.4, 15.7, and 4.4 nM, respectively. This is ten times more effective than both HDAC inhibitor Vorinostat and EGFR inhibitor Erlotinib, and displays comparable activity against HER2 to Lapatinib, an inhibitor of HER2. In addition, when treating cancer cells, CUDC-101 increases the acetylation of p53 and α-tubulin; non-histone HDAC substrates. The results indicate that CUDC-101 effectively inhibits all three targets in cancer cells. CUDC-101 exhibits broad antiproliferative activity in many types of human cancer cells, including cancer of the lungs, pancreas, liver, colon, breast, prostate, and head and neck. Phase I clinical trials showed that the drug is well tolerated by patients and exhibits antitumor activity (Shimizu et al. 2014). However, phase II clinical trials were not conducted.

Inhibition of CUDC-10 was found for both the full length androgen receptor (flAR) and the androgen receptor of variant 7 (AR-V7), upon which prostate cancer resistant to complete sterilization depends (Sun et al. 2016). The effect of CUDC-101 on flAR and AR-V7 was shown to be duplicated only by other HDAC inhibitors or by killing HDAC isoforms HDAC5 and HDAC10. Thus, inhibition of HDAC signaling reduces the activity of flAR and AR-V7.

The design, synthesis, and biological evaluation of a 64Cu-labeled agent (compound 47) for imaging HDAC in positron emission tomography, obtained by introducing a chelator by click reaction with CUDC-101 and then radiolabeled Cu-64 (Fig. 15) is reported (Meng et al. 2013).

Fig. 15
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Agent for PET based on CUDC-101

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The antitumor activity of CUDC-101 in combination with gemcitabine in pancreatic cancer has recently been investigated (Ji et al. 2018). In general, the combination of CUDC-101 and gemcitabine significantly increased antitumor activity when compared with gemcitabine alone, which provides the basis for studying the combination of gemcitabine and CUDC-101 as a potential therapeutic strategy for pancreatic cancer.

Potential therapeutic compounds

Among the drugs that have potential therapeutic activity and require further testing and implementation in medical practice, it should be noted that new classes of substances with the structure of 4-(3H)-quinazolinone and acylated hydroxamic acids (compound 48) (Bratu et al. 2014) and quinazoline-2,4(1H, 3H)-dion derivatives (compounds 49 and 50) with a hydroxamate group are candidates for detecting antitumor activity (Fig. 16) (Zhou et al. 2013). Efficient and selective inhibitors of the enzyme Fe(II) peptide deformylase (PDF) E. coli (compound 51) were obtained by rational optimization of a weakly binding screening hit (hydrazide 5-chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl) acetic acid (Apfel et al. 2001). However, it is noted that the synthesized compounds showed moderate antibacterial activity in vitro.

Fig. 16
figure 16

Compounds with potential therapeutic activity

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Conclusion

Quinazoline and hydroxamic acids create various classes of biologically active compounds with great therapeutic potential. The simplicity of their preparation, flexibility of structural modifications, and multifunctionality provide them with cause for widespread use; both for practical and research purposes. A number of currently available drugs are based on quinazoline/hydroxamic acid frameworks. Moreover, the combination of these two different pharmacophore groups in one molecule can lead to the creation of a drug that is more effective from the point of view of the combination of pharmaceutical properties and will allow the synthesis of a huge number of new compounds with promising properties.

It is interesting to note that among the latest available developments, many are dedicated to their promising antitumor activity. The strategy for creating multifunctional drugs is actively developing throughout the world and is promising in creating new-generation drugs, as evidenced by a number of studies presented in available literature. Among hybrid compounds of quinazoline and hydroxamic acid, selective inhibitors of MMPs and HDACs have been found.

The revealed synergistic effect of inhibiting EGFR, HER2, and HDAC has allowed a new method to develop multipurpose inhibitors of VEGFR-2/HDAC and EGFR/HER2/HDAC. One of the successful developments in this group of inhibitors, the CUDC-101 compound, has currently completed phase I clinical trials. The uniqueness of hybrid multifunctional compounds lies in the fact that they act on several targets responsible for the development of tumors. This reduces the resistance of the tumor to drugs and toxicity of drugs, and significantly increases the effectiveness of treatment.

However, the biological activity of the quinazoline/hydroxamic acid hybrid compounds is certainly not limited only to the antitumor effect. Interest in this group of compounds is constantly growing; a number of antibacterial and fungicidal preparations are currently under development. One of the latest favorable developments is the quinazoline–benzoate MTB-AHAS inhibitors, which are the basis for the development of potent anti-tuberculosis drugs. Also, within the last decade, active research is in progress to create a class of new antiviral drugs designed to treat influenza, hepatitis C, and other viral infections.

Thus, such compounds, due to the uniqueness of the set of properties of pharmacophore fragments, have high potential as the basis for the development of effective drugs.