**1. Introduction**

The design of highly complex spiro-heterocycles with multifunctional and potential pharmaceutical efficacy has attracted considerable attention from synthetic and medicinal chemists [1]. One of the most privileged *aza*-heterocyclic sca ffolds is spiro[pyrrolidine-oxindole] [2], which is present in natural products and useful as a building block for the synthesis of significant biologically active compounds. This class of *aza*-heterocyclic compounds has gained grea<sup>t</sup> interest, owing to several reports of its pharmaceutical potency, including anticancer [3], antitumor [4], 5-HT3 receptor antagonist [5], acetylcholinesterase-inhibitory [6], antibacterial [7], antibiotic [8], and MDM2–p53 inhibitor [9] e ffects; selective cyclooxygenase COX-1 with TNFα and IL-6 inhibitors [10]; and potential hypoglycemic dual

inhibitory activity against α-amylase and α-glucosidase [11] (Figure 1). To date, prolonged efforts have been exerted to expand divergent complexity and to develop efficient synthetic routes for these valuable privileged *aza*-heterocyclic scaffolds, which would remarkably enhance their bioactivity [1,12]. In particular, [3+2] cycloaddition is one of the most efficient synthetic approaches to produce these valuable scaffolds with stereoselective method and high yield [13]. To extend our previous research, we explored the effect of halogen substitution on the isatin ring.

**Figure 1.** Natural (Spirotryprostatin A and B) and other synthetic spirooxindole scaffolds with high biological importance and structure-activity relationship.

Our previous studies [9] revealed that the presence of dihalide substitution on acyl moiety substantially increased the anticancer activity of the resulting product(s). Moreover, it was reported [9] that chlorinated indole moiety retained better activity, as illustrated in Figure 1a. Subsequently, this study was designed to introduce two bromo atoms on the indole ring, presumably to enhance the activity of the examined spirooxindole compounds shown in Figure 1. The *aza*-heterocyclic

compounds were prepared via a multicomponent eco-friendly strategy using oxindole as a core structure. The resulting hybrids were biologically evaluated using an *in vitro* antiproliferative assay against three different cell lines for liver, breast, and colorectal cancer. In addition, molecular properties and lipophilicity studies were conducted to ge<sup>t</sup> insight about "drug properties consideration" and to discover the compounds' structure-property relationship (SPR).

### **2. Results and Discussion**
