Synthesis, crystal structure, DFT, docking and biological activity studies of (NZ,N’Z)-3,3’-(piperazine-1,4-diyl)bis(N-(-4-methyl benzylidene)propane-1-amine)

Highlights

• Novel imine compound is synthesized and characterized by IR, NMR and UV technique.

• The compound showed a monoclinic crystal structure with unusual C–H…π interaction.

• DFT and Hirshfeld surface analysis is employed to study the crystal packing.

• The compound showed an excellent antimicrobial, antioxidant and anticancer activity.

Abstract

The title compound (NZ,N’Z)-3,3’-(piperazine-1,4-diyl)bis(N-(-4-methyl benzylidene)propane-1-amine) (PMP) was synthesized by reacting N,N′-bis(3-aminopropyl)piperazine and 4- methyl benzaldehyde using microwave energy. The formed compound is characterized using FTIR, ¹H and ¹³C NMR, UV–visible and elemental analysis techniques. Single crystal X-ray diffraction confirms that the title compound crystallizes in a monoclinic crystal system with space group of P2₁/c. The unusual C–H…π interaction facilitate the crystal packing proved by the Density Functional Theory (DFT) and Hirshfeld surface analysis. The PMP showed an excellent result against Enterococcus Faecalis with the value of 3.125 μg/ml. The antioxidant behavior of PMP showed strong antioxidant property. The in silico docking studies on breast cancer cell BRCA1 protein confirms that the PMP showed excellent binding affinity value of −6.80 kcal/mol. The lipophilicity of the molecule is high due to the non polar nature of the PMP. The in vitro anticancer studies on the breast cancer cell line MDA MB-231 showed promising results.

Introduction

Imines are the compound which forms by the condensation reaction of the amine and the aldehyde or ketone leads to a class of a well known group of materials called as Schiff base. N,N′-bis(3-aminopropyl)piperazine (BAPPA) is a class of compounds which plays an important role in pharmaceutical industries. Generally, the piperazine ring exists in two forms, namely, boat and chair [1]. The piperazine can easily react with the carbonyl group which leads to the Schiff base. Different synthetic methods have been proposed by several workers [[2], [3], [4]] for the synthesis of Schiff bases. In conventional methods, solvents and elevated temperatures have been used for the preparation of the Schiff bases [2,[4], [5], [6]]. However, the reactivity of the piperazine is fast and can easily react with the carbonyl compounds. It can also be prepared by other methods using microwave, grinding method, etc. Among the available methods, microwave method is less time consuming as significant quantitative yield can be achieved with high purity. Piperazine based Schiff bases have wide applications in the fields such as antimicrobial agents, non-linear optical materials, catalyst, etc. [3,4,7,8]. They are also used for the preparation of metal complexes due to the fact that it contains multidentate donor sites in its molecular structure [9]. Many reports are available in the literature related to the synthesis of metal complex based on piperazine containing Schiff bases [1,5,10,11]. In recent times, the crystals of piperazine such as piperazine (bis) p-toluene sulfonate, Piperazin-1-ium 4-aminobenzenesulfonate, 1,4-bis(3-ammoniopropyl)piperazine-1,4-diiumbis[dichromate(VI) and N,N′-bis(4-chlorobenzylidene)-1,4-bis(3-aminopropyl)piperazine has been reported [2,[12], [13], [14]].

Among many applications shown by the piperazine molecule, biological application is found to be the most important nowadays due to the resistance shown by the microorganism towards available drugs. The enhanced antimicrobial activity of the Schiff base compounds due to the presence of ring structure in piperazine [1,10,15]. Reactivity of a CN group of imines is involved in the formation of complexes with enzymes due to Pi electron donor ability [16]. They show good co-ordination or interaction with biological entities like DNA, RNA, Lipid, Protein, etc. and therefore they inhibit or accelerate the biological process. The interaction between the drug molecule and that of the targeted cell receptors can be conveniently studied by the Molecular docking method which is proven as reliable and accurate. Virtual screening of the drug candidate can be studied by the in silico method and this provide enormous scope in the novel drug discovery [17]. This virtual screening method operates on the basis of ease in which the targeted cell binds with the drug molecules, i.e., binding of cell with the drug molecule in a preferred orientation leading to the formation of stable complex [18].

The mutation of two well known gene such as BRCA1 and BRCA2, have been identified as a gene responsible for 80% of early-onset breast cancers. In most cases, breast cancers have been developed due to the defects in the gene such as BRCA1 or BRCA2 [19]. Among two genes, BRCA1 is considered to be more vulnerable to the defects [20] and therefore BRCA1 protein was tested against the compounds PMP and compared with standard anti breast cancer drug as Gefitinib through bio-computational analysis. The result of in silico method is compared with the Invivo anticancer result obtained from the cell line of MDA MB-231 cancer cell.

Due to this unique advantage of piperazine based Schiff bases, herein we are reporting the synthesis and characterization of the piperazine based Schiff base using the unconventional microwave method. The obtained product is well characterized and nearly quantitative yield has been achieved within a few minutes. The piperazine base crystallized as needles and the crystal is examined by the X-ray diffraction method and DFT based Hirshfeld surface analysis was done to prove the unusual C–H…π interaction. Further, the intermolecular interactive force between the aromatic ring to that of C–H is studied by the use of Molecular electrostatic potential (MESP) based on Merz-Kollman analysis. The obtained crystal is further examined for the possible use as an antimicrobial drug and the interaction between the drug and the microbes is discussed in detail. In silico docking study on BRCA1 breast cancer cell have been estimated and in vitro anticancer activity is evaluated on the MDA MB-231 cancer cell line. The obtained biological result have been correlated with the characteristic feature of the PMP molecule.