1
Introduction to Ivermectin

Aeyaz Ahmad Bhat1, Atif Khurshid Wani2, Tahir ul Gani Mir2* and Nahid Akther2

1School of Chemical Engineering and Physical Sciences, Lovely Professional University, Phagwara, Punjab, India

2School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India

Abstract

Ivermectin (IVM), an antiparasitic drug, has a wide range of biological applications. Taking its spectrum of actions into consideration along with the significant safety and efficacy it was approved by USFDA in 2015 and made available as a generic medicine. In addition to cancer, it is used to treat number of bacterial and viral infections in humans. IVM takes part in several biological operations, making it a potential treatment option for a variety of viruses, including SARS-CoV-2. The antiviral activity of IVM has been studied in vitro and in vivo. The target sites of IVM in its actions against viruses and cancerous cells include viral replication and cell cycle progression respectively. This chapter provides an overview of the sources and synthetic scheme involved in IVM building besides elucidating its therapeutic potential. There have been very few reports on the toxic effects of IVM that have been published so far. However, some of the concerns related to its toxicology have been delineated in this chapter.

Keywords: Ivermectin, pharmacology, antibacterial, anticancer, antiviral, COVID-19, toxicity

1.1 Introduction

Ivermectin (IVR) belongs to the group of broad-spectrum antiparasitic agents which have a unique mode of action and is currently authorized to be used for the treatment of onchocerciasis, lymphatic filariasis, strongyloidiasis, scabies and head lice [1]. Recently, it has been shown that IVR can also exhibits a lot of new interesting activities such as antibacterial, antiviral and anticancer. IVR acts as a positive allosteric regulator of several channels including the glutamate-gated chloride channel (GluCl), ?-aminobutyric acid type-A receptor, glycine receptor, neuronal a7-nicotinic receptor, and purinergic P2X4 receptor. In most of the IVR-sensitive channels, the effects of IVR include the potentiation of agonist-induced currents at low concentrations and channel opening at higher concentrations [2]. In vertebrates, IVR also functions as a positive allosteric regulator of a number of ligandgated ion channels. Glycine receptor (GlyR), ?-aminobutyric acid type-A receptor (GABAAR) and neuronal 7-nicotinic receptor are all activated or modulated by submicromolar concentrations of IVR (nAChR). The specific binding and high affinity of this compound to the GluCl channels found in the nerve and muscle cells of invertebrate animals is strictly related to its anti-parasitic activity. This causes the nerve or muscle cell to become hyperpolarized, increasing the permeability of the cell membrane to chloride ions, which causes the parasite to become paralyzed and die. Because some mammals lack GluCl channels, IVR has a very low affinity for mammalian GluCl channels and does not bind to them; these three facts serve as the foundation for its activity.

IVR appears to be safe for use in humans, but there have been reports linking the drug to parasympathetic disturbances (salivation, dilation of pupils) [3-5]. Along with its well-known anti-parasitic properties, IVR has also recently been shown to have strong anti-cancer properties, suggesting that it may be useful in the treatment of a number of cancers [6]. IVR exhibits anti-cancer properties due to its capacity to block the Wnt/TCF pathway, AKT/mTOR, and MDR (multidrug resistance) proteins (transcription factor of T-cells). One of the main oncogenic kinases, PAK-1 (p21-activated kinase), is degraded as a result of IVR [7]. By blocking Wnt-TCF, it is effective in treating lung, skin, and colon cancer as well as glioma multiforme, melanoma, and glioma [8]. IVR causes autophagy, a self-destructive effect in breast cancer, as demonstrated by Dou et al. studies using breast cancer cell lines, animal models, and 20 patient breast cancers have shown that reduced autophagy of breast cancer cells is associated with decreased expression of PAK-1 because of ubiquitin-mediated degradation. Inhibiting PAK-1 prevented Akt from becoming phosphorylated, which blocked the Akt/mTOR signaling pathway and slowed the growth of tumors [9].

1.2 Sources and Synthesis

Ivermectin (IVR) is a 22,23-dihydro derivative of avermectin B1 formed by the Streptomyces avermitilis bacterium from macrocyclic lactone (Figure 1.1). Besides IVR the other was approved for human use in the year 1987 by FDA [5, 10]. The general synthetic route is achievable by performing selective catalytic hydrogenation at C22-C23 as highlighted in Scheme 1.1.

IVR is a nonhygroscopic, crystalline powder that ranges in color from white to yellow-white and has a melting point of about 155°C. The respective empirical formulas are C48H74O10 and C47H72O14, with the molecular weights of 875.10 and 861.07.

Ivermectin B1a and B1b have very similar chemical structures; Ivermectin B1a has an ethyl group at the C-26 position, while B1b has a methyl group.

Figure 1.1 Chemical structure of Ivermectin.

Scheme 1.1 Avermectin and IVR chemical structures.

Scheme 1.2 Synthesis of synthetically important synthon of IVM.

IVR is made up of at least 80% B1a and no more than 20% B1b. A very important structural moiety or a "synthon" of the important drug IVM can be synthesized in lab by adopting the following synthetic procedure as depicted in Scheme 1.2. The mild thermally induced cycloaddition of two aromatic compounds, 3,4-bis(benzyloxy)furan (1) and 2-(himethylsilyl) ethyl coumalate (2) is a crucial constructive step in the synthesis of the synthon (11) and results in an 88% yield of the chromatographically separable endo and exo adducts (3,4). Although the isomerization at C-24 may present challenges, the conversion of the endo adduct 4 to 11 is initially investigated despite the fact that both adducts are potentially useful intermediates for the synthesis of the synthon. The synthesis was further carried out by the reaction of the derivative (5) which was reduced to derivative (6). Derivative (6) was further bought under the well-known concept of Witting reaction to yield the compound (7). Reaction with base and further oxidation of the derivative (7) generated derivative (10) that was finally reduced in the last step of the reaction to generate the synthetically importantly synthon (11) in good yield.

1.3 Pharmacological Potential of Ivermectin

1.3.1 Ivermectin in the Treatment of Cancer

1.3.1.1 Ovarian Cancer

The fifth most common cause of cancer-related death in women is epithelial ovarian cancer. The therapeutic options for epithelial ovarian cancer have remained largely unchanged for more than 30 years, despite improvements in the treatment of many malignancies. Patients with ovarian cancer frequently receive platinum-based chemotherapy, such as cisplatin, but these treatments have a poor prognosis. This is probably because there is significant intra and inter tumor heterogeneity at the molecular and epigenetic levels [11, 12]. Sequencing has shown that TP53 mutations are frequently found in epithelial ovarian tumors, and that low-frequency mutations in the genes NF1, BRCA1, BRCA2 and RB1 are also present [13]. For better clinical management of ovarian cancer, new therapeutic approaches or agents are required. Let us start the pharmacological profile of the Ivermectin with the most important breakthrough which was provided by Zhang et al. The studies were carried out and it was found that by inhibiting Akt/mTOR signaling, Ivermectin improves the in-vitro and in-vivo effectiveness of cisplatin in treating epithelial ovarian cancer. In spite of specific cellular and molecular variations, Ivermectin inhibited growth in the G2/M phase and induced caspase-dependent apoptosis in ovarian cancer. The inhibitory effect of cisplatin on ovarian cancer cells was dramatically enhanced by Ivermectin in a dose-dependent manner. Ivermectin inhibited, in ovarian cancer cells, the phosphorylation of essential molecules in the Akt/mTOR signaling pathway. In addition, Ivermectin-induced inhibition of Akt/ mTOR, growth arrest, and apoptosis were restored by overexpressing constitutively active Akt. Ivermectin alone significantly slowed tumor growth in a mouse model of ovarian cancer xenograft. Tumor growth was completely stopped when combined with cisplatin throughout the course of treatment without any side effects. Additionally, the Ivermectin concentrations used in our study are pharmacologically feasible.

1.3.1.2 Renal Cell Cancer

The proximal tubules of nephrons give rise to the epithelial tumor known as renal cell carcinoma (RCC), which is resistant to radiotherapy and chemotherapy [14, 15]. Patients with metastatic RCC still experience relapses as the disease worsens, despite the fact that targeted therapy significantly improved their clinical outcomes [16]. Therefore, patients who experience post-operative relapse or who have RCC that has spread to other organs require novel and potent therapeutic approaches. Recent research has shown that many cancers...