Quinazoline and Its Derivatives: Privileged Heterocyclic Scaffolds in Antileishmanial Drug Discovery

Abstract

Leishmaniasis is a parasitic disease caused by protozoa belonging to the genus Leishmania. Over one billion people are living in areas endemic to leishmaniasis and are at risk of infection. Each year, more than one million new cases are reported. Although few drugs are available for the treatment of leishmaniasis, none of them are ideal due to their high resistance and toxicity risk. Many compounds with quinazoline scaffold were synthesized and reported to have promising antiparasitic and antileishmanial activities. This review aims to evaluate the reported antileishmanial activities of quinazoline and its derivatives with a special focus on their structure-activity relationships.

1. Introduction

Quinazolines are aza-derivative of quinolone and represent a large group of heterocyclic compounds that are composed of a fused benzene ring and a pyrimidine ring, also known as 1,3-diazanaphthalene. Quinazolinones and quinazolinediones are quinazolines in which one and two carbonyl groups, respectively, are present on the pyrimidine ring and are the most commonly encountered quinazoline derivatives. Quinazolinone has two isomers: quinazolin-2-one and quinazolin-4-one (Figure 1).

Figure 1.

Quinazoline, quinazolinones, and quinazolinedione structures.

2. Antileishmanial quinazoline derivatives

One of the first publications on the therapeutic potential of quinazolines was the development of folic acid analogs in which the pteridine ring was replaced by quinazoline for acute leukemia treatment and immunosuppression (Figure 2) [1]. The research group synthesized 2,4,6-trisubstituted compounds that were prepared as analogs of the folic acid/pteridine ring [2]. These compounds were reported as folate antagonists against parasitic diseases such as Chagas disease and malaria. PAM 1392 was also tested against Trypanosoma cruzi (Figure 2) [3]. 2,4,6-triaminoquinazoline (TAQ), first identified by Davoll as an antiparasitic agent, functions as a folic acid analog (Figure 2) [4]. The antileishmanial potential of TAQ as a Leishmania major pteridine reductase inhibitor was reported by McLuskey et al. [5].

Figure 2.

Folic acid and reported quinazoline derivatives with antitrypanosomal and antileishmanial activity [1, 2, 3, 4, 5, 6, 7].

Mendoza-Martínez et al. reported a series of TAQ derivatives with in vitro antileishmanial activity against Leishmania mexicana. Their first article reported N⁶-monosubstituted compounds. Among them, N⁶-(ferrocenmethyl)quinazolin-2,4,6-triamine (H2) showed activity against promastigotes and intracellular amastigotes and low cytotoxicity in mammalian cells (Figure 2) [6]. Their second article reported N⁶-mono- and disubstituted TAQ derivative compounds. The compounds were designed based on docking studies on the Leishmania dihydrofolate reductase and pteridine reductase enzymes. Among them, Compound 6 and Compound 9 had the lowest LC₅₀ against L. mexicana promastigotes (Figure 2) [7].

Berman et al. synthesized 2,4-diaminoquinazoline derivatives and evaluated their antileishmanial activity against L. major amastigotes in human monocyte-derived macrophages. Compounds 1 and 2 showed IC₅₀ values of 12 and 91 pg./mL, respectively (Figure 3) [8]. This group also measured the inhibitory activities of the compounds of the Leishmania DHFR enzyme; however, the results were not well correlated with antileishmanial activity. One of the positive controls used in the study, the quinazoline derivative trimetrexate (TMQ), which is a dihydrofolate reductase inhibitor used against pneumocystis pneumonia, was inactive against amastigotes in this model (Figure 3).

Figure 3.

TMQ and reported quinazoline derivatives with antileishmanial activity [8, 9].

Khabnadideh et al. investigated the inhibitory effects of a series of 2,4-diaminoquinazolines against the L. major dihydrofolate reductase and evaluated their antileishmanial activity against axenic L. donovani amastigotes. An alkene derivative, compound 12, was the most potent against L. donovani with high selectivity compared to mammalian L6-cells. The authors reported little correlation between enzyme inhibition and parasite growth (Figure 3) [9].

Since several studies have identified trypanothione and the trypanothione system and its role in the oxidative stress defense mechanisms of the Kinetoplastida Leishmania and Trypanosoma, it has been a target in antileishmanial and antitrypanosomal drug discovery [10].

A series of 2-piperazin-1-yl-quinazolin-4-ylamine derivatives were reported and tested as antitrypanosomal and antileishmanial lead drug candidates against trypanothione reductase (TR) by Cavalli et al. (Compound 14, Figure 4) [11]. Docking of the quinazoline core showed interactions with the TR active site. However, there was a poor correlation between enzyme inhibition and trypanocidal activity.

Figure 4.

Reported quinazoline derivatives with antitrypanosomal and antileishmanial activity [11, 12, 13].

Patterson et al. reported 3,4-dihydroquinazoline analogs as TR inhibitors as new antitrypanosomal agents. The compounds were tested against the bloodstream form of T. brucei and MRC-5 cells for toxicity in mammals. Compounds 6 k and 29a were reported as good starting points for further structure-based drug design studies (Figure 4) [12].

Chauhan et al. reported new β-carboline–quinazolinone hybrid as inhibitors of L. donovani TR and antileishmanial activities against extracellular promastigotes and intracellular amastigotes of L. donovani [13]. Compounds 8 k, 8 l, and 8n were the most active with high selectivity compared to mammalian cells and were also potent TR inhibitors, showing good activity against intracellular amastigotes (Figure 4).

Kumar et al. reported a series of a new class of 4-(hetero)aryl-2-piperazino quinazolines and assessed their in vitro activity against extracellular promastigotes and intracellular amastigotes of L. donovani [14]. Compound 4ab, which is hardly selective in antileishmanial assays, showed low IC₅₀ values in antiproliferative assays (Figure 5). However, the replacement of indole moiety with an aryl ring in the form of 2,3-dimethoxybenzene (compound 4cb) and 2,3,5 trimethoxybenzene (compound 4bb) together with an N-methyl group remarkably enhanced the antileishmanial activity (Figure 5).

Figure 5.

Reported quinazoline derivatives with antileishmanial activity [14, 15, 16, 17].

Kabri et al. reported quinazoline derivatives with antiplasmodial, anti-toxoplasmic, and antileishmanial activity. Compound 19 showed moderate antileishmanial activity against L. donovani promastigotes (Figure 5) [15].

Arfan et al. reported the antileishmanial activity of 2,3-disubstituted-3H-quinazolin-4-one derivatives [16]. The compound 3-benzyl-2-phenylquinazolin-4(3H)-one (compound 11) was found to be more potent against L. major promastigotes than the positive control and is therefore expected to be a more effective leishmanicidal candidate (Figure 5).

Sharma et al. carried out studies on 2,3-dihydroquinazoline, tetrahydroquinazoline, and their ferrocene derivatives [17]. Compounds 8a, 8 g, and 9f showed very consistent and promising leishmanicidal activity against intracellular amastigotes as well as in vivo efficacy in the golden hamster model and did not show any toxicity to macrophages and Vero cells (Figure 5).

Birhan et al. synthesized compounds that showed significant antileishmanial activities compared to standard drugs [18]. (E)-2-(4-Chlorostyryl)-3-p-tolyl-4(3H)-quinazolinone (compound 7) was the compound with the most promising antileishmanial activity (Figure 6). It is approximately 4 and 250 times more active than the standard drugs amphotericin B and miltefosine, respectively.

Figure 6.

Reported quinazoline derivatives with antitrypanosomal and antileishmanial activity [18, 19, 20, 21, 22].

Van Horn et al. reported the antileishmanial activity of a series of N²,N⁴-disubstituted quinazoline-2,4-diamines [19]. The compounds were tested for in vitro antileishmanial potency against intracellular L. donovani and L. amazonensis parasites. The potency of compounds 15, 16, and 23 against intracellular antimony-resistant clinical isolate L. donovani and antimony-sensitive isolate L. donovani was also evaluated (Figure 6). These results led to the testing of compounds 15, 16, and 23 in an in vivo murine visceral leishmaniasis model. While compounds 15 and 16 had no activity in vivo, compound 23 reduced parasitemia by 37% when administered intraperitoneally at 15 mg/kg/day for 5 consecutive days.

Zhu et al. investigated N²,N⁴-disubstituted quinazoline-2,4-diamines as novel antileishmanial agents [20]. Based on their in vitro antileishmanial potency, N⁴-benzyl-N²-(4-chlorobenzyl)quinazoline-2,4-diamine (15a) and N²-benzyl-N⁴-isopropylquinazoline-2,4-diamine (40a) were selected for in vivo pharmacokinetic and antileishmanial evaluation (Figure 6).

Katiyar et al. reported that the 4-anilinoquinazolines canertinib and lapatinib, which are kinase inhibitors, killed bloodstream T. brucei in vitro with a low micromolar range [21]. Patel et al. studied lapatinib analogs, which provided an excellent starting point for optimizing the new antiparasitic chemotype [22]. One of these compounds, compound 23a (NEU617), was reported to be a potent inhibitor of T. brucei growth (Figure 6).

Woodring et al. also investigated lapatinib analogs [23]. They replaced the quinazoline scaffold with [3,2-d] and [2,3-d] thienopyrimidine. They found that the compounds were active against T. cruzi, L. major amastigotes, and P. falciparum. The most potent analog of all scaffolds against L. major amastigotes was compound 4e. Only the thieno[3,2-d]pyrimidine derivatives showed a sub-micromolar activity against L. major promastigotes (Figure 7).

Figure 7.

Reported quinazoline derivatives with antitrypanosomal and antileishmanial activity [23, 24, 25, 26, 27].

Saad et al. reported 4-arylamino-6-nitroquinazoline derivatives with antileishmanial activities [24]. Among all the derivatives, compounds 21 and 8 showed excellent antileishmanial activities; they were more active than the tested standard (Figure 7).

Enciso et al. have studied quinazolin-2,4-diones as new antileishmanial agents [25]. Compound 6e displayed an attractive profile, including antileishmanial activity against L. Mexicana, which was superior to the positive standard, with high selectivity over a macrophage cell line (Figure 7).

Macedo et al. reported that when Glucantime® was incubated with the quinazoline derivative QNZ (a TNF-α blocking agent and NF-κB inhibitor), a higher activity was observed against the growth of amastigotes (Figure 7) [26].

Agarwal et al. reported fused quinazoline derivatives and tested them against L. donovani promastigotes [27]. Among the compounds tested, compound 6 l was reported to be the most active compound (Figure 7).

3. Conclusions

Quinazoline and quinazolinone scaffolds are one of the privileged scaffolds of medicinal chemistry. Among the various activity reports, we tried to summarize the reports that showed antiparasitic activity, especially antileishmanial activity. According to these reports, compounds containing quinazoline-quinazolinone have promising antileishmanial activity. Compounds with this scaffold are an important starting point in the search for antileishmanial drug candidates.

Conflict of interest

The author declares no conflict of interest.