An overview of pyridazin-3(2H)-one: a core for developing bioactive agents targeting cardiovascular diseases and cancer

Abstract

Cardiovascular diseases (CVDs) and cancer are the top two leading causes of death globally. Vasodilators are commonly used to treat various CVDs. In cancer treatment, targeted anticancer agents have been developed to minimize side effects compared with traditional chemotherapy. Many hypertension patients are more prone to cancer, a case known as reverse cardio-oncology. This leads to the search for drugs with dual activity or repurposing strategy to discover new therapeutic uses for known drugs. Recently, medicinal chemists have shown great interest in synthesizing pyridazinone derivatives due to their significant biological activities in tackling these critical health challenges. This review will concentrate on pyridazin-3(2H)-one-containing compounds as vasodilators and anticancer agents, along with a brief overview of various methods for their synthesis.

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Plain language summary

Article highlights.

Introduction

• Cardiovascular diseases are the major cause of death worldwide, vasodilators of different classes are used to relieve these cardiovascular diseases.

• Cancer is the second leading cause of death worldwide and different chemotherapeutic agents were synthesized to target many receptors.

• Since cancer and CVDs share the same risk factors, therefore many patients with hypertension are prone to cancer, a case known as reverse cardio-oncology. Thus, discovery of drugs with dual effects or repurposing strategies to discover a new activity for a known drug may be a tool to obtain new candidates to overcome cancer and CVDs.

Biological activities of pyridazin-3(2H)-one derivatives

• Pyridazin-3(2H)-one scaffold is found in many derivatives with different biological activities.

Pyridazin-3(2H)-ones as vasodilators

• Pyridazin-3(2H)-ones as vasodilators: There are many examples of vasodilators in the market bearing pyridazin-3(2H)-one core. Moreover, in the literature, many pyridazinone derivatives are acting as direct vasodilators or targeting renin-angiotensin-aldosterone and phosphodiesterase.

Anticancer activity of pyridazin-3(2H)-one derivatives

• There are different examples of pyridazinone derivatives in the market and literature acting as anticancer through the inhibition of PARP, DHFR, B-RAF, BTK, FGFR, FER and Tubulin polymerization.

Possible strategies for the synthesis of pyridazin-3(2H)-one

• Different strategies for the synthesis of various pyridazinone derivatives were described.

1. Background

Cardiovascular diseases (CVDs) are the main cause of death worldwide, they result in predictable 17.9 million deaths annually, representing 32% of all worldwide deaths. Heart attacks and strokes were responsible for almost 85% of these deaths [1]. CVDs are also Europe's leading cause of death, accounting for 47% of all female fatalities and 39% of all male deaths [2]. The term “CVDs” refers to a group of conditions that affect the heart and blood vessels, including cerebrovascular disease, coronary heart disease and rheumatic heart disease. Strokes and heart attacks cause more than four out of five deaths caused by cardiovascular disease, with premature deaths accounting for a third of these deaths among people under the age of 70. By 2030, CVDs will be responsible for the deaths of nearly 22.2 million people annually. Nowadays, low- and middle-income countries (LMICs) have 75% of CVD deaths, resulting in a 7% drop in these countries gross domestic product (GDP) [1].

This global health problem can be overcome by using different classes of vasodilators including angiotensin-converting enzyme (ACE) inhibitors like ramipril [3], angiotensin-II antagonists such as losartan [4], calcium-channel blockers like amlodipine [5], nitrates as isosorbide dinitrate [6], direct vasodilators as hydralazine [7] and phosphodiesterase 5 (PDE 5) inhibitors as Sildenafil [8,9]. Unfortunately, many of these drugs have a variety of side effects, including fluid retention, headaches, acute pulmonary edema and excessive hair growth [10]. Therefore, developing agents with high vasodilator efficacy and few adverse effects remains a critical demand in medicinal chemistry.

Moreover, cancer, the second leading cause of death exceeded only by CVDs, is considered a major public health problem [11]. In the United States (US), about 1.9 million new cancer cases are diagnosed in 2023 with approximately 609,820 deaths from cancer which is about 1,670 deaths per day. Breast, lung and colorectal cancers are the most common cancer types in women while prostate and lung cancers affect men [11]. Additionally, in 2023, about 9,910 children (ages 0 to 14 years) and 5,280 adolescents (ages 15 to 19 years) were diagnosed with cancer and 1,040 children and 550 adolescents died from the disease. The most diagnosed cancers in children and adolescents are leukemia (28 and 13%, respectively); brain, including benign and borderline malignant tumors (26 and 21%); and lymphoma (12% and 19%) [11]. Cancer can be prevented and controlled by following evidence-based strategies for cancer diagnosis and early detection, treatment and palliative care [11]. Targeted chemotherapy is preferable to traditional therapy due to its higher efficacy and lower side effects [12,13]. However, the emergence of drug resistance motivated medicinal chemists to design new targeted, more potent therapies that can overcome the existing resistance and toxicity.

The tendency of kinases to activate multiple signaling pathways of cancer cell survival, proliferation and metastasis has made them a promising molecular target for cancer treatment [12,13]. The clinically approved drugs: erlotinib and lapatinib are examples of targeted epidermal growth factor receptor (EGFR) kinase inhibitors indicated for the treatment of lung cancer and breast cancer, respectively [14]. Additionally, in 2023, three tyrosine kinase inhibitors have been approved by the US FDA for new indications; first, in July, quizartinib (Vanflyta) was approved for treatment in patients with newly diagnosed acute myeloid leukemia (AML). Quizartinib targets the kinase FLT3, which is mutated in around a third of AML cases. Second, in August, the FDA granted full approval of pralsetinib (Gavreto) for patients with metastatic non-small cell lung cancer (NSCLC) in which the RET gene has fused with another gene. The third drug is bosutinib (Bosulif) that has been approved in September by the FDA for certain pediatric patients with chronic myelogenous leukemia (CML). Bosutinib targets BCR-ABL and is approved to treat CML that harbors the fusion protein. To be eligible for bosutinib, the cancer must also be in the chronic phase (an early stage of CML) and must be newly diagnosed or resistant or intolerant to prior CML therapies [15].

It is worth noting that several studies have recently illustrated a correlation between hypertension and cancer incidence and mortality [16–18]. Thus, a survey indicated that patients with cardiovascular disease are more prone to cancer compared with the other population [19]. Additionally, a meta-analysis of thirteen prospective studies revealed that high blood pressure was related to a 7% higher risk for breast cancer [20]. This may be because these health problems have the same risk factors as obesity and diabetes mellitus [21]. The association of these two health problems is known as reverse cardio-oncology and it represents an interesting field for both clinicians and medicinal chemists [22]. However, in literature, few studies are focusing on developing agents with dual effects to be effective for treating reverse cardio-oncology [23]. Meanwhile, there is a recent strategy of drug repurposing to discover new therapeutic uses for known drugs, thus, several vasodilators have been found to exhibit anti-proliferative effects on different cancer cells [24]. Therefore, in this review, the promising pyridazin-3(2H)-one scaffold was selected due to its variable biological activities. Here, we focus on pyridazin-3(2H)-one-containing derivatives with vasodilator and anticancer activities. This may highlight the possibility for dual activity of such derivatives, so they can be screened later to confirm their dual activity. Furthermore, different synthetic pathways are discussed to shed light on accessible routes to obtain them in high yield.

1.1. Pyridazin-3(2H)-one scaffold

Pyridazin-3(2H)-one is a six-member heterocyclic scaffold, with two adjacent nitrogen atoms and a carbonyl group at position 3, this leads to tautomerism (Figure 1).

Figure 1.

Structure of pyridazine-3(2H)-one and its tautomerism.

However, the keto form of pyridazinones is found more common than the enol form (3- and 4-hydroxyl pyridazines) [25], this is because the keto forms are more stable (Figure 1) [26].

1.2. Biological activities of pyridazin-3(2H)-one derivatives

Pyridazin-3(2H)-one is an interesting core for many bioactive agents with different biological activities [27]. Furthermore, the ability of this core to interact with multiple targets such as nuclear receptors, ion-channel coupled receptors, G-protein coupled receptors and different enzymes attracts the interest of medicinal chemists. Several studies on this advantageous scaffold resulted in the synthesis of powerful molecules with diverse biological activities including vasodilator [28,29], antiplatelet aggregation [30–32], cardiotonic [33], antidiabetic [34], antitubercular [35,36], antimicrobial [36], antidepressant [37], anticonvulsant [38], analgesic [39,40], anti-inflammatory [40–42], antiproliferative [43–45], anti-asthmatic [46] and anti-HIV-1 [47].

Because of the ring's various pharmacological effects, many researchers worldwide are working on developing different pharmacologically active medicines bearing it. Recent advances achieved by researchers to overcome CVDs and cancer are detailed below.

1.2.1. Pyridazin-3(2H)-ones as vasodilators

Vasodilator medications can manage many cardiac disorders, the most common of which is systemic hypertension in addition to coronary vascular diseases (CVDs), including myocardial infarction, heart failure, chronic renal disease, stroke and angina [48,49].

There are numerous pyridazin-3(2H)-one derivatives have been synthesized as vasodilators, some of them are in clinical trials and others are approved as a medication in the market.

1.2.1.1. Pyridazin-3(2H)-one derivatives in the market with vasodilator activity

There are a lot of pyridazin-3(2H)-one derivatives with CVS activities that have entered a clinical trial. For example, the l-isomer of Bemoradan (RWJ-22867) (1) is a potent positive inotropic agent that inhibits cardiac phosphodiesterase III. It was undergoing phase II trials with Ortho-McNeil Pharmaceutical (Johnson & Johnson) in the US for the treatment of heart failure, where 0.88 mg of Bemoradan increased cardiac output by 40%, and dose-dependently reduced systemic vascular resistance (SVR) and pulmonary capillary wedge pressure (PCWP) without increasing heart rate. However, no recent development of Bemoradan has been reported [50]. Furthermore, Indolidan (2) is a potent inotropic vasodilator acting by selective inhibition of PDE IV in cardiac membranes. However, a double-blind placebo-controlled study in heart failure patients did not reveal clinical benefit. Therefore, clinical development of this compound has been stopped [51]. Imazodan (3) is a cardiotonic agent by selective inhibition of cardiac cyclic adenosine monophosphate (c-AMP) phosphodiesterase with IC₅₀ = 8 μM [52,53]. Levosimendan (4) is an inodilator indicated for the short-term treatment of acute decompensated severe chronic heart failure, and in cases where conventional therapy is not considered adequate. It acts by increasing the cardiac contractility via calcium sensitization of troponin C. It also has vasodilation and cardio-protective effects that are related to the opening of sarcolemmal and mitochondrial potassium-ATP channels, respectively. Data from clinical trials indicate that Levosimendan improves hemodynamics with no attendant significant increase in cardiac oxygen consumption and relieves symptoms of acute heart failure; these effects are not impaired or attenuated by the concomitant use of beta-blockers [54–56]. Pimobendan (5) is widely used for the treatment of dogs with congestive heart failure (CHF) and preclinical degenerative mitral valve disease (DMVD) with cardiomegaly (Figure 2) [57,58].

Figure 2.

Some pyridazinone-based vasodilator drugs.

1.2.1.2. Pyridazin-3(2H)-one derivatives in literature with vasodilators activity

Pyridazin-3(2H)-one scaffold has been reported to exert significant vasodilator activities through different mechanisms as follows:

1.2.1.2.1. Pyridazin-3(2H)-one as direct-acting vasodilators

In 1988, a dihydropyridazinone series was synthesized with expected antihypertensive, vasodilating and adrenoceptor antagonist activities [59]. After intravenous bolus delivery, the dose required to generate a 50% increase in blood flow to the auto-perfused hindquarters of anesthetized normotensive rats was estimated using a dose-response curve. All compounds showed promising vasodilator activities, especially compound 6 which was selected as a novel candidate, as it acted as a direct vasodilator, (with ED₅₀ = 1.6 μmol/kg) [59].

In addition, in 2004, Demirayak et al. [60] succeeded to synthesize pyridazinone derivatives. Compound 7 was examined for its in vitro vasodilating properties using sheep carotid arteries and using the tail-cuff method for the in vivo assay. It revealed an excellent activity as a vasodilating agent (%inhibition = 33.04).

Moreover, some pyrrole-substituted aryl pyridazinones were prepared and screened for their antihypertensive activity in vitro using an isolated rat aorta and the results revealed that compounds 8a and 8b were the highest effective derivatives with 48.8, 44.2% inhibition of phenylephrine contraction, respectively [61].

Also, in 2009, Bansal et al. [62] synthesized some 6-(4-carboxymethyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone amide derivatives, these compounds were screened for their vasodilatory action. The vasodilator potential of pyridazinone ring replacement at the 2-position has also been investigated. Compound 9 revealed the highest vasodilatory action (IC₅₀ = 0.051 μM).

Moreover, in 2010, Costas et al. [63] prepared novel pyridazinone derivatives and screened them as vasodilators and antiplatelet drugs. The N, O-dibenzyl derivative (10) was found to be the most active compound based on the analysis of biological data (IC₅₀ = 35.3 μM) (Figure 3).

Figure 3.

Structures of some pyridazine-3(2H)-one-based direct-acting vasorelaxants.

Along with this, in 2011, Mishra et al. [64] synthesized some novel dihydropyridazin-3(2H)-ones, and the tail-cuff method was used to examine the antihypertensive activity. In comparison to propranolol (41.40%) and hydralazine (40.76%), compounds 11 and 12 were able to reduce mean arterial blood pressure (MABP) by (41.84 and 40.98%), respectively.

In 2013, a series of dihydropyridazin-3(2H)-ones was prepared by Bansal et al. [65] and tested for their vasodilatory effects on rat thoracic aortic rings. Compound 13 exhibited a vasorelaxant activity with an inhibitory activity (IC₅₀ = 0.199 μM) compared with hydralazine (IC₅₀ = 0.316 μM).

Besides, in 2010, Siddiqui et al. [29] prepared a variety of novel dihydropyridazin-3(2H)-ones and they used the tail-cuff technique to assess their vasodilation efficacy. Compounds 14 and 15 showed a reduction in mean arterial blood pressure (MABP) by 41.99 and 42.40%, respectively, being more effective than the gold standard hydralazine which decreased MABP by 40.76%.

It's worth mentioning that Allam et al. [66] in 2020 synthesized a group of pyridazin-3(2H)-one-based compounds and evaluated their vasodilating activities using rat thoracic aortic rings. In comparison to hydralazine (EC₅₀ = 18.210 μM), the most active molecules were the acid (16), its ester analog (17) and 4-methoxyphenyl hydrazide derivative (18) (EC₅₀ = 0.339, 1.225 and 1.204 μM, respectively).

Meanwhile, in 2020, 6-fluoroarylpyridazinone derivatives were synthesized and screened for their vasorelaxant activity. The potency of the compounds was compared with the activity of prazosin with IC₅₀ = 0.487 μM, and the most potent compound was compound 19 with IC₅₀ = 0.250 μM (Figure 4) [67].

Figure 4.

Structures of some pyridazine-3(2H)-one derivatives with direct vasodilator activity.

1.2.1.2.2. Pyridazin-3(2H)-one as an antagonist of the renin-angiotensin-aldosterone system

Angiotensin-converting enzyme (ACE) is an enzyme involved in the etiology of hypertension as it is responsible for angiotensin II formation with vasoconstriction effect [68]. Molecular docking studies in 2016 [69] were performed by a group of researchers to determine which pyridazinone molecule was the most effective in lowering blood pressure. The Dojindo ACE Kit-WST assay showed that Compound 20, which had the highest docking scores, had a promising ACE inhibitory activity (IC₅₀ = 5.78 g/ml) compared with that of lisinopril (IC₅₀ = 0.85 g/ml). According to the results of this investigation, the ACE inhibitory action of pyridazinone derivatives can be improved by adding amino and carboxylic acid groups to their structures.

1.2.1.2.3. Pyridazin-3(2H)-one as phosphodiesterase inhibitors

Phosphodiesterase enzymes are essential for removing the phosphate group from the target cell and lowering cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) levels. Inhibiting these enzymes also limits the breakdown of cAMP or cGMP, resulting in smooth muscle relaxation, vasodilation and bronchodilation [70,71].

In 1987, a series of pyridazin-3(2H)-ones and similar compounds were tested for their ability to inhibit distinct types of phosphodiesterases (PDE) isolated from guinea pig ventricular muscle in vivo [72]. These 4,5-dihydropyridazones showed a strong inhibitory effect on cardiac type III phosphodiesterase. The inhibition of cardiac type I and type II phosphodiesterase, which hydrolyzes cyclic AMP and cyclic GMP, was insignificant. Compound 21a, a 5-methyl derivative of Imazodan, was the most specific PDE III inhibitor, having an IC₅₀ of 0.6 μM. Meanwhile, the 4,5,6,7-tetrahydrobenzimidazole analog, compound 21b, was the most effective PDE III inhibitor, with an IC₅₀ of 0.15 μM, in comparison to milrinone a reference standard (IC₅₀ = 2.5 μM).

It is worth mentioning that Kanojia et al. [73] in 1988 evaluated a series of 6-benzoxacinyl pyradazin-3-ones for their suppression of cardiac PDE-III fraction, both in vitro and in vivo. Compound 22 was discovered to be a very effective and selective PDE-III fraction inhibitor (IC₅₀ = 10 μM) in addition to an orally active and long-acting potent inotropic vasodilator activity.

In 2002, Piaz and colleagues [74] synthesized a series of pyrazolo[3,4-d]pyridazinones and tested them for their PDE-5 inhibitory activity. The obtained structure-activity relationship (SAR) concluded that the best results were found when the pyrazole backbone was fused with the pyridazinone moiety as in compounds 23a,b. Furthermore, the presence of a benzyl at the pyridazine 2-nitrogen was associated with potent and selective inhibitory activity toward PDE5. Compound 23a has the greatest activity among the synthesized analogs, as it had an IC₅₀ value of 0.14 μM, whereas the introduction of a branched alkyl chain instead of the methyl of the pyrazole in compound 23a resulted in compound 23b, the activity unchanged (IC₅₀ = 0.18 μM) but enhanced its selectivity versus PDE6. The IC₅₀ of the reference standards used in this study, Zaprinast and Sildenafil, were 1.0 μM and 0.005 μM, respectively.

Furthermore, Abouzid et al. [75] in 2008 synthesized three series of pyridazinones to find possible vasodilatory cardiotonic lead molecules. Compounds 24a,b fitted the proposed pharmacophoric model for cAMP PDE inhibitor. Milrinone was used as a reference standard to examine the vasorelaxant action in the rabbit's isolated major pulmonary artery. The target compounds' properties were inspired by the design of various biologically active lead compounds that inhibit cAMP phosphodiesterase III, such as Milrinone. Compounds with a better match to the anticipated pharmacophore were developed. Both compounds 24a,b exhibited % inhibition = 14.50%, while compounds 25a-f revealed % inhibition = 25, 22.67, 21.50, 18.50, 34.33 and 36.17%, respectively. The novel synthesized compounds' vasodilator action was tested on the isolated rabbit pulmonary artery. Compared with the standard drug, Milrinone (% inhibition = 60.50%), these tested compounds demonstrated moderate vasorelaxant activity. Unfortunately, there was no obvious correlation between the substituents and the biological activity of the compounds.

Additionally, Kumar et al. [76] in 2008 synthesized dihydropyridazin-3(2H)-one derivatives as powerful inotropic and vasodilating agents. The compounds were tested for cardiotonic action in isolated rat atria and vasorelaxant activity in the descending thoracic aortic rings of Wistar rats precontracted with phenylephrine (10^-6 mol/l). Compound 26 had a considerable vasorelaxant action (IC₅₀ = 0.08 μmol/l), compared with hydralazine a reference standard (IC₅₀ = 0.316 μmol/l).

Moreover, a new series of pyrazolo[1’,5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones was prepared and tested for their PDE-5 inhibition. It was found that compound 27 revealed a potent and selective inhibition of PDE-5 (IC₅₀ = 34 nM for PDE5 and 42.5% inhibition for PDE-6 at 2 μM) compared with Sildenafil (IC₅₀ = 20 nM for PDE-5, 40 nM for PDE-6) [77]. The structure-activity relationships (SAR) observed in this study suggested that a phenyl ring at position 9 of the tricyclic core was necessary for PDE5 inhibitory activity. Moreover, modifications of substituents at position 6 revealed interesting results, thus, the 2-pyridinyl derivative showed a very good balance of potency and selectivity versus PDE5 (IC₅₀ = 81 nM for PDE5 and 21.3% at 2 μM for PDE6). The potency, together with the selectivity, decreased when a 3-pyridyl ring was inserted, but a complete loss of activity was observed for the 4-pyridyl derivative, suggesting that the nitrogen could be involved in a specific bond. In addition, the 6-phenyl derivative exhibited an analogous potency (IC₅₀ = 81 nM) to 2-pyridinyl analog, but with lower selectivity. However, the best results were associated with the introduction of branched chains (compound 27) which showed a significant improvement in the potency of the corresponding 6-methyl derivative. This compound appeared particularly interesting because of its high activity toward PDE5 associated with very good selectivity. Finally, the existence of benzyl moiety at position 3 was crucial for the activity.

Recently, Abd-Rabo et al. [78] synthesized new 2-phenyl-3,6-pyridazinedione derivatives as potential inhibitors for PDE-5 enzyme. It was found that compound 28 revealed a potent inhibition of the PDE-5 enzyme (IC₅₀ = 22 nM) compared with Sildenafil (IC₅₀ = 16 nM). It was found that the presence of an electron-withdrawing group at the arylidene ring was more favourable for the activity than the electron-donating moiety (Figure 5).

Figure 5.

Structures of some pyridzin-3(2H)-one derivatives with PDE inhibitory activity.

1.2.2. Anticancer activity of pyridazin-3(2H)-one derivatives

Cancer is among the most prevalent and dangerous diseases, involving abnormal cell growth and creating a severe threat to everyone's health globally. Cancer has been determined to be society's second-largest cause of mortality, trailing only cardiovascular diseases. As a result, the cancer death rate has grown worldwide seriously [79,80]. Although radiation, surgery and cytotoxic chemotherapy are used to treat cancer in its early stages, however, there is no more successful strategy for complete eradication. In the last few years, cancer treatment has shifted to targeted anticancer drugs that are selective for specific forms of cancer, for example, breast cancer, colon cancer, blood cancer, ovarian cancer, kidney cancer and lung cancer [81,82]. Anticancer medicines that target specific proteins, enzymes, or receptors inhibit malignant cells from growing and dividing [83]. As a result, scientists are seeking novel anticancer scaffolds by discovering new biological targets that are more selective in targeting cancer cells, resulting in high efficacy and less adverse reactions.

The pyridazinone scaffold is emerging as an important and viable core for the development of potent anticancer medicines that work by targeting many pathways in cancer cells [84].

1.2.2.1. Pyridazin-3(2H)-one derivatives in the market with anticancer activity

There are a lot of pyridazin-3(2H)-one derivatives in the market that have anticancer activities as Olaparib (29) which is used for treatment of ovarian cancer with IC₅₀ = 0.015 μM [85], Fluzoparib (30) for treatment of breast, ovarian and gastric cancer with IC₅₀ = 1.46 nmol/l [86], Simmiparib (31) is a PARP1/2 inhibitor with twofold more potent than Olaparib [87], Talazoparib (32) has anticancer activity against breast and prostate cancer with IC₅₀ = 0.0002 μM [88], and E-7016 (33) is selective to melanoma with IC₅₀ = 0.04 μM [89], all of these drugs act as PARP inhibitors. Also, Tepotinib (34) is effective in the case of solid tumors with IC₅₀ = 0.001 μM by acting through inhibition of C-met kinase (Figure 6) [90].

Figure 6.

Pyridazin-3(2H)-one-based anticancer drugs.

1.2.2.2. Pyridazin-3(2H)-one derivatives in literature with anticancer activity

Pyridazin-3(2H)-one scaffold has been reported to exert significant anticancer activities by acting on different targets as summarized below:

1.2.2.2.1. Dihydrofolate reductase inhibitors

Folates are extremely vital elements that play an important role in nucleotide formation. Dihydrofolate (DHF) is converted to tetrahydrofolate (THF) as a cofactor by dihydrofolate reductase (DHFR). Tetrahydrofolate induced cell proliferation by performing a novel synthesis of thymidylate (TMP) and purine [91–93]. Because it is evident that cell death occurs owing to DHFR function loss, dihydrofolate reductase inhibitors are a significant enzyme targeting the enhancement of chemotherapy [94,95]. These antifolates can be classified into classical and nonclassical antifolates including piritrexim (PTX), methotrexate (MTX) and trimetrexate (TMQ) [96–100].

Ewida's research group synthesized various novel 1,3-thiazoles and thiazolo[4,5-d]pyridazine derivatives in 2018 [101]. The compounds in this group were investigated for antineoplastic and DHFR inhibitory activities in vitro. In this study, it was found that the electronegativity of the substituents on the phenyl rings at positions 3 and 8 had a crucial role in controlling the activity. That, at position 3- the order of activity was 4-BrPh >4-CH₃Ph >4-CH₃OPh; while at position 8- the order of activity was Ph >4-CH₃Ph >4-BrPh >4-CH₃OPh. Thus, compound 35 inhibited DHFR with IC₅₀ values of 0.06 μM and displayed increased potency against OVCAR-3 ovarian cancer and MDA-MB-435 melanoma with IC₅₀ values of 0.32 and 0.46 μM, respectively.

1.2.2.2.2. B-RAF inhibitors

B-Raf protein is a serine-threonine receptor that plays an important part in signaling pathways by activating RAS-RAF-MEK-ERK and aids in cell progression. Nearly ninety percent of B-Raf muted cancer cells have the typical V600E oncogenic mutation, which includes a mutation at codon 600 by replacing glutamic acid with valine, and nearly 7% of all human cancer cells have this muted B-Raf kinase [102–106]. Deregulation of the B-Raf signaling system led to the overexpression of many cancer types, including prostate cancer (10%), colorectal (15%), melanoma (60%), mammary gland (10%) and hepatocellular (14%). Three B-Raf inhibitors approved by the USFDA are sorafenib, dabrafenib and vemurafenib [107,108].

In 2020, Thabit et al. [109] tested three novel series of phenyl dihydropyridazinone derivatives for their cytotoxicity against numerous cell lines. When compared with sorafenib (IC₅₀ 44.05 nM), the thiourea series showed the highest affinity to B-Raf with IC₅₀ values ranging from 24.97 to 35.59 nM. Compound 36 has an IC₅₀ value equal to 24.79 nM, demonstrated the highest cytotoxicity and B-Raf affinity, and inhibited the cell cycle at the G2-M phase, with significant apoptotic activity. In molecular modeling investigations, these chemicals demonstrated a favourable binding relationship with the B-Raf enzyme predictably. The structure-activity relationship revealed the importance of the thiourea linker for B-Raf affinity. Moreover, N-phenyl substitution on the pyridazinone ring improved the inhibitory activity relative to the non-substituted analogs.

1.2.2.2.3. Bruton tyrosine kinase inhibitor

Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase enzyme that belongs to the Tec family. Several studies have shown that overexpression of BTK may result in B-cell activation, proliferation, differentiation, survival and maturation via downstream signaling of the BCR and Fcγ receptor (FcR). Therefore, inhibiting the BTK signaling pathway is becoming an increasingly appealing therapeutic target in the treatment of hematological malignancies and rheumatoid arthritis (RA) [110–113]. Ibrutinib was recently identified as a strong BTK inhibitor, it is the first-in-class irreversible BTK inhibitor licensed by the US FDA for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia and Waldenstrom's macroglobulinemia [114].

In 2019, Zhang et al. [115] synthesized a new series of pyrazolo[3,4-d]pyridazinone derivatives, which were subsequently tested against the BTK enzyme. Compound 37 displayed a strong action against the BTK enzyme following series optimization with good pharmacokinetic results (IC₅₀ = 2.1 nM).

1.2.2.2.4. Fibroblast growth factor receptors inhibitor

FGFRs are tyrosine kinase receptors composed of four (FGFR 1–4) tyrosine kinase receptors that exist in the cell membrane. Angiogenesis, wound healing, embryonic development, cell proliferation and differentiation all are dependent on FGFRs [116–123].

Wu's group published a novel pyrazolo[3,4-d]pyridazinone derivatives that are potent FGFR covalent inhibitors in 2021 [124]. Compound 38 showed strong enzymatic activity against FGFR by the FGFR signaling pathway suppression. Furthermore, at a dose of 50 mg/kg, this drug demonstrated a stronger anticancer effect (tumor growth inhibition value (TGI) = 91.6%), leading to tumor immobility in the FGFR1-driven NCIH1581 xenograft model.

1.2.2.2.5. FER tyrosine kinase inhibitors

In the FES family, FER is a non-transmembrane receptor tyrosine kinase. It plays a vital role in cell motility via cortactin phosphorylation and interaction with phosphatidic acid [125–127]. Overexpression of MAN2A1-FER has been found to promote cell propagation and intrusiveness in cancers such as prostate cancers, liver cancers, non-small cell lung cancers, ovarian cancers, glioblastoma multiforme and esophageal adenocarcinoma. According to recent literature reports, FER is being investigated as a potential target for anticancer therapy [128].

In 2019, Taniguchi et al. [129] carried out an initial SAR research on HTS hits, followed by chemical modification of the pyridine ring by scaffold hopping, resulting in the identification of compound 39 (DS21360717), which demonstrated in vivo anticancer activity in a subcutaneous tumor model (IC₅₀ = 0.49 nM).

1.2.2.2.6. PARP inhibitors

Poly ADP-ribose polymerase (PARPs) are nuclear enzymes composed of eighteen proteins that perform critical roles in DNA repair, apoptosis, transcriptional control, genomic integrity, histone binding and stability of chromosomes [130,131]. PARP enzymes are divided into two types: PARP-1 and PARP-2. Both enzymes play critical roles in the genome repair mechanism [132]. Thus, PARP inhibitors have been considered as a prospective cancer target since they are implicated in programmed cell death and DNA integrity. PARP-1 inhibitors have attracted significant interest in the development of innovative viable anticancer medicines with promising anticancer activities [133]. Overexpression of PARP-1 has been seen in a few malignancies, including melanomas, lung cancer, pancreatic cancer, prostate cancer and breast cancer. Many studies are being conducted to determine the role of PARP-1 inhibitors in the treatment of solid malignancies [133]. PARP inhibitors have lately shown potential in the treatment of advanced ovarian cancer and BRCA breast cancer. Olaparib, Rucaparib and Niraparib are the FDA-approved PARP-1 inhibitors on the market. PARP inhibitors are a viable molecular target for cancer therapy since they act as both radio and chemical sensitizers [133]. As a result, there is a critical need to develop powerful PARP inhibitors that are effective in cancer treatment.

Ferrigno et al. [134] performed SAR investigations on pyridazin-3(2H)-one derivatives in 2010, which resulted in the development of a novel scaffold of PARP-1 inhibitors with outstanding enzyme activity in BRCA-1 defective cells. The SAR elucidated that the proline residue was essential for the activity, additionally, preparation of the enantiomers of 40 revealed that the (R) isomer was more active than the (S) enantiomer both in PARP-1 enzyme (IC₅₀ = 1.3 vs 3.8 nM) and antiproliferation (CC₅₀ = 45 and 780 nM, respectively) assays.

In addition, Zhu et al. in 2012 [135] announced a new class of tetrahydropyridopyridazinones as PARP-1 inhibitors. The SARs demonstrated that the presence of the NH in the tetrahydropyridyl ring improved the in vivo pharmacokinetic characteristics compared with the tetrahydrophenyl congeners. Moreover, the weakly basic amine analogs with an aryl- or heteroaryl group at the para-nitrogen of the piperazine ring resulted in a series of the most active PARP inhibitors. Thus, compound 41 demonstrated the highest binding affinity toward the PARP-1 enzyme, with a Ki = 0.4 nM and cellular EC₅₀ = 1.0 nM.

Furthermore, in 2018, different phthalazinone-based derivatives were developed and screened for their PARP-1 inhibition. It was observed from the obtained results that the substitution pattern on the aniline moiety has a great impact on the PARP-1 inhibitory activity. Appending lipophilic m-substituents at the aniline moiety is more beneficial than the p-substitutions and di-substitutions for the suppressive activity toward PARP-1; regardless of the type of N-2 linker (acetyl or propionyl) and the type of substitution at C-4 of the phthalazinone core (phenyl or benzyl). Therefore, compound 42 emerged as the most potent PARP-1 inhibitor with an IC₅₀ value of 97 nM, compared with that of Olaparib (IC₅₀ = 139 nM) (Figure 7) [136].

Figure 7.

Structures of pyridazine-3(2H)-one-based derivatives with PARP inhibitory activity.

1.2.2.2.7. Tubulin polymerization inhibitors

Microtubules are composed of alpha beta-tubulin heterodimers that link together to produce head-to-tail protofilaments. Straight and parallel protofilaments can also be connected laterally to form a microtubule hollow cylinder [137]. These drugs either inhibit or promote microtubule polymerization. Tubulin inhibition is one of the most popular targets for cancer treatment. Colchicine, Vincristine, Combretastatin A-4 (CA-4) I and podophyllotoxins are examples of naturally occurring compounds that attach to the colchicine site and inhibit tubulin polymerization, resulting in cancer cell necrosis [138–142]. Recent research indicated that pyridazinones have a considerable inhibitory effect on tubulin cellular localization. Thus, Abdelbaset et al. in 2018 [143] synthesized a new series of pyridazin-3(2H)-one derivatives with a quinoline moiety. All these synthesized compounds were tested for their cytotoxicity using a single dosage against 60 cell lines following the NCI procedure. Compound 43 showed full death of cells against the renal cancer cell line and the non-small cell lung cancer cell line and revealed IC₅₀ of 2.9 and 2.2 μM against human pancreas cancer cell line panc-1 and, paca-2 respectively.

2. Possible strategies for the synthesis of pyridazin-3(2H)-one

Since pyridazin-3(2H)-one scaffold is of high interest to medicinal chemists due to its wide range of biological effects, its synthesis is of great necessity. So, new and intriguing approaches for manufacturing pyridazin-3(2H)-one derivatives have evolved. The development of simple and effective procedures for the synthesis of pyridazin-3(2H)-one derivatives from readily available precursors is crucial.

Several procedures for preparing the pyridazin-3(2H)-one moiety are discussed in this review, where the reactions of furanones, diketones, ketoacids, or ketoesters with hydrazine hydrate or its derivatives results in various pyridazinones. These methods presented different reaction conditions and starting materials to gain the target pyridazin-3(2H)-one derivatives.

First, Coates and McKillop [144] adopted a method in 1993 to obtain different 6-substituted 3(2H)-pyridazinones (45) using one pot reaction between different acetophenones (44), glyoxylic acid and hydrazine hydrate (Figure 8).

Figure 8.

Synthesis of 6-subestituted 3(2H)-pyridazinones (45).

Additionally, in 2012, Murty et al. [145] published a procedure for the synthesis of a novel series of pyridazin-3(2H)-one derivatives (49). 3-(Aroyl)-propionic acid (46) was reacted with substituted aromatic aldehydes in acetic anhydride in the presence of anhydrous sodium acetate to produce substituted furanone-based intermediates (47). Furanones derivatives (47) were then reacted with hydrazine hydrate in the presence of ethanol to produce the hydrazide derivative (48), which was subsequently treated with 1N HCl in benzene to produce the pyridazin-3(2H)-one derivatives (49). The final product was obtained in high yield and purity (Supplementary Figure S1).

Using 4-hydrazinobenzenesulfonamide hydrochloride (53) and an appropriate aroylacrylic acid (52) in the presence of ethanol, researchers were able to synthesize a novel series of benzenesulfonamide-linked pyridazinone derivatives (54) in 2012 [146]. The Friedel-Craft acylation process was utilized by reacting substituted benzene (50) with maleic anhydride (51) as starting materials to produce an aroylacrylic acid (52), which was then reacted with 4-hydrazinobenzenesulfonamide (53) to give pyridazinone derivatives (54). The yield of the final derivatives ranged between 40.2% and 72.8% (Supplementary Figure S2).

In addition, the substituted 1,2-dihydropyridazine-3,6-dione (56) intermediate was synthesized by Elagawany et al. [147] in 2013 by refluxing hydrazine sulfate with 3-phenylmaleic anhydride (55) affording pyridazindione intermediate (56). To produce substituted 3,6-dichloro-1,2,3,6-tetrahydropyridazine (57), this intermediate (56) was refluxed with phosphoryl chloride. Compound 59, a substituted pyridazin-3(2H)-one derivative, was then obtained by subjecting the dichloro product (57) to different primary amines yielding 58a,b which were treated with glacial acetic acid and sodium acetate to afford 59 in a good yield (Supplementary Figure S3).

Meanwhile, in 2015, Kamble et al. [148] prepared a new family of pyridazin-3(2H)-ones. First, 2,3-dichloro-4-oxobut-2-enoic acid (60) was heated under reflux with 2-(3-chloro-4-fluorophenyl),1-phenylhydrazine (61), in the presence of methane sulfonic acid in ethanol to give the dichloropyridazinone derivative (62). Then compound 63 was produced by the reaction of 4,5-dichloropyridazin-3-one derivative (62) with cyclized saturated/aliphatic amines in acetonitrile in good yields ranging from 65%–90% (Supplementary Figure S4).

Also, Kim et al. [149] described the synthesis of the pyridazin-3(2H)-one derivative (68) as shown in (Supplementary Figure S5). First, a solution of 5-bromo-2-chloropyrimidine (64) was stirred with the morpholine derivative (65) in ethanol in the presence of N,N-diisoprpylethylamine (DIPEA) to yield S-(4-(5-bromopyrimidin-2-yl)morpholin-2-yl) methanol (66). Then, reacting (66) with toluene sulfonyl chloride in dimethyl amino pyridine in the presence of triethyl amine afforded the toluene sulfonyl derivative (67). This was reacted with the pyridazinone derivative to give the target compound (68) with a good yield and purity (Supplementary Figure S5).

In a Friedel-Crafts acylation reaction environment, Abdelbaset et al. [143] synthesized pyridazin-3(2H)-ones linked quinolone derivatives (72) utilizing benzene (50) and succinic anhydride (69) as starting materials. The first reaction yielded 3-benzoyl propionic acid (46), which then reacted with quinolone aldehydes (70) in the presence of acetic anhydride and a few drops of triethylamine to yield the corresponding furanones (71). The quinolone-linked furanone were refluxed with hydrazine monohydrate (98%) in absolute ethanol for twenty-four h to obtain substituted pyridazin-3(2H)-ones (72) (Supplementary Figure S6).

Moreover, in 2018, Bouchmaa et al. [150] used benzo[b]furan-2-yl-carboxaldehydes (76) to synthesize pyridazin-3(2H)-one derivatives (78). Substituted salicylaldehydes (74) were produced via formylation of substituted phenols (73) with chloroform in the presence of sodium hydroxide. Salicylaldehyde derivatives (74) were then heated under reflux in dimethylformamide with bromacetaldehyde diethylacetal in the presence of potassium carbonate, giving 2-(2,2-diethoxyethoxy)benzaldehydes (75). These benzaldehydes (75) were cyclized to benzo[b]furan-2-ylcarboxaldehydes (76) in the presence of acetic acid. To make substituted 3-benzo[b]furan-2-yl-methylene-levulinic acids (77), benzo[b]furan-2-yl-carboxaldehydes (76) were refluxed with levulinic acid in ethanol. At last, pyridazin-3(2H)-one derivatives (78) were produced by reacting 3-benzo[b]furan-2-yl-methylene-levulinic acids (77) with hydrazine hydrate in ethanol. Although the intermediate step yield was poor, the final compounds yield ranged between 69% and 87% (Supplementary Figure S7).

Additionally, Zare et al. [151] reported the ultrasound-promoted multicomponent synthesis of pyridazinones (79) starting from arenes (50), succinic anhydride (69) and arylhydrazine (61) in the presence of an efficient recyclable catalyst such as 1-butyl-3-methylimidazolium bromochloroaluminate ([bmim]Br-AlCl₃), where the pyridazinones (79) were obtained in a high yield and after short reaction time (Supplementary Figure S8).

Furthermore, Alex et al. [152] have developed a one-pot process for the synthesis of 6-methyl-2-phenyl-4,5-dihydropyridazin-3(2H)-one (81). The reaction involved hydrohydrazination and condensation of phenylhydrazine (61) and 4-pentynoic acid (80) in the presence of one equivalent of ZnCl₂ to give the target pyridazinone derivative (81) (Supplementary Figure S9).

Also, Stepakov et al. [153] demonstrated a microwave technique for the synthesis of 4-(N-aryl)carbamoylmethyl-4,5-dihydropyridazin-3(2H)-ones (85) by reaction of N-aryl substituted maleimide (82) with azines (83). In some cases, Michael addition intermediates (84) were isolated, which were then converted into the corresponding 4,5-dihydropyridazin-3(2H)-ones (85) under solvent-free microwave conditions (Supplementary Figure S10).

3. Conclusion

Cardiovascular diseases and cancer are the leading causes of death globally, posing significant health challenges. This urgent health crisis drives researchers and medicinal chemists to innovate, designing and synthesizing various derivatives targeting specific receptors to achieve maximum efficacy with minimal toxicity. Given the shared risk factors between these diseases, discovering dual-activity agents could be pivotal in addressing reverse cardio-oncology. Pyridazin-3(2H)-one emerges as a particularly intriguing scaffold due to its diverse biological activities. This review highlights the significance of pyridazin-3(2H)-one derivatives as promising vasorelaxant and anticancer agents. By exploring the activities of various pyridazinone analogs on different targets, this review serves as a valuable resource for researchers. It guides them in investigating these derivatives' potential dual activity and synthesizing new pyridazinone-based compounds to tackle the reverse cardio-oncology challenge.

4. Future perspective

Cardiovascular diseases and cancer represent two major health problems that motivated medicinal chemists to discover the key targets associated with these health problems and find different small molecules acting on biotargets to combat these diseases. Pyridazin-3(2H)-one scaffold was found in many derivatives in the market and literature acting as vasorelaxants or anticancer agents. Therefore, it can be considered a promising core for the synthesis of many active vasorelaxants and anticancer agents with high efficacy and lower side effects.

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/17568919.2024.2379234

Author contributions

ZS Abd-Rabo: writing the draft of this review. AM Serry: revising and editing the review. RF George: conceptualization, revising, editing and approving the review to be submitted to the journal.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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No writing assistance was utilized in the production of this manuscript.