Macrocyclic molecules are molecules bearing at least 12 atoms with a cyclic skeleton, and they have unique spatial structures and physicochemical properties [1]. Macrocyclic ligands containing nitrogen heteroatoms separated by various organic bridges have been studied for many decades. Examples are porphyrin and its analogs, which are the metal-binding sites in many metalloenzymes, hemoglobin, and other naturally occurring compounds. It has a significant influence on the fields of chemical biology, materials chemistry, medicinal chemistry, bioorganic chemistry, drug development, host–guest chemistry, and bioactive natural products [2], [3], [4], [5], [6]. Interestingly, triazole macrocycles can form various non-covalent interactions, such as Van der Waals forces, hydrogen bonding, dipole–dipole, and hydrophobic interactions, with various biological targets with a high affinity. In this regard, these motifs are considered to be critical units for synthesizing various biologically active constructs, as they can also enhance water solubility. Macrocycles comprising triazole cores are worthwhile scaffolds in various fields, especially in materials, medicinal, pharmaceutical and supramolecular chemistry [7], [8], [9]. They can act as chemosensors, molecular receptors, peptidomimetics, drug carriers, and enzyme inhibitors and show exciting features, such as self-assembling and anion-binding properties [10], [11], [12], [13], [14].

Macrocyclic molecules generally have more constrained conformations to control their conformational flexibilities. These rigid conformations allow them with strong binding affinities and high selectivity to target proteins. Macrocyclization of quinazoline-based epidermal growth factor receptor (EGFR) inhibitor allows it highly selective to EGFR mutant proteins [15]. Their unique conformational features offer macrocyclic molecules special drug characteristics compared to traditional small-molecular drugs and large biologic. The remarkable advantages of macrocyclic molecule drugs have made them one of the hot spots for medicinal chemistry in the past 20 years.

Breast cancer is one of the most common types of malignancies in women worldwide. Breast carcinogenesis is unrecognized because of a variety of risk factors in the context of bio-molecular dynamics. The risk of breast cancer has increased in the past 50 years and accounts for 23 % of all cancer deaths in Asia according to the statistical reports of WHO (2012) [16]. Cancer is caused due to genetic damage in cells which show faulty division and mutation. Breast cancer is a type of hormonal cancer. Breasts contain glandular tissues which are highly sensitive to hormonal changes in the body [17]. Breast cancer chemotherapy is marked by targeting the function of receptors such as ERα (estrogen receptor alpha), PR (progesterone receptor), EGFR (epidermal growth factor receptor) etc. Estrogen receptors (ER) play a vital role in the initiation and progression of breast cancer.

Macrocycles were reported to display antitumor properties, which may be attributed to the inhibition of different enzymes involved in carcinogenesis cases. Abd El-Galil E. et al. have synthesized a series of macrocyclic pyrido-pentapeptide candidates from N-bis-[1-carboxy-2-(benzyl)]-2,6-(diaminocarbonyl)pyridine The in-vitro cytotoxicity activity was investigated for all compounds against MCF-7 and HepG-2 cell lines comparison to Tamoxifen and 5-Fluorouracil as positive control [18]. Ahmed H. M. et al prepared a series of new benzosubstituted macrocyclic-diamides containing pyridine as the subcyclic unit and their corresponding dithiodiamide derivatives [19]. In 2019, Engelhardt et al discovered a series of macrocyclic EGFR TKIs which potently inhibit lung tumors [20]. Biamonte M.A et al. have been dedicated to the discovery of Hsp90 inhibitors, and their research ultimately led to a series of 2-aminobenzamides exhibiting low nanomolar potency in proliferation assays [21].

The ω-benzyloxy-substituted suberoyl-based hydroxamic acid was discovered by Auzzas et al., in 2007 [22]. Chen et al. reported a conformationally constrained macrocyclic peptidomimetic as a potent signal transducer and activator of transcription 3 (STAT3) inhibitor via click chemistry [23]. A small-molecule antagonist that can block the dimerization of STAT3 is a very attractive therapeutic approach for cancers. In 2021, Xu et al. reported a conformationally constrained Glutaminase 1 (GLS1) macrocyclic inhibitor targeting antiproliferative activity against HCT116 cells and MDA-MB-436 cells [24]. Zapf et al. described the discovery of macrocyclic inhibitors of the ATP-dependent molecular chaperone Hsp90, a well-established target in oncology [25], [26], [27].

Cyclization of a linear molecule into a macrocyclic ring constitutes a significant change in molecular shape, biological activity, and drug-like properties. Compared with an acyclic linear molecule, cyclized molecules have better physicochemical properties, such as good solubility, lipophilicity, metabolic stability, bioavailability and overall pharmacokinetics [28].

Most of the macrocyclic drugs currently on the market are natural products with complex structures. The complex structure increases the difficulty of synthesis and the cost of production, leading the pharmaceutical industry to be cautious about the development of macrocyclic drugs [29]. To overcome this, we have herein synthesized new macrocyclic ligand 1, 1′, 3, 3′ Bis − [2,3,5,6-Tetramethyl-p phenylenebis(methylene)]dibenzotriazlinium dibromide hydrate (BTD) and investigates drug likeness and the toxicity of the ligand BTD have been studied by utilizing ADMET (Adsorption, Distribution, Metabolism, Excretion, and Toxicity) investigation. Molecular docking simulations were also performed to determine the compound’s interaction with various proteins in order to identify pharmacological properties. To understand the anticancer, anti-tuberculosis and DNA binding properties of BTD, molecular docking studies were performed and the results were compared with the experimental ones.