A rational Drug Design Journey toward Dual Biological Activity and an Exploration for Enhanced Delivery Using the Macrocycles Cucurbit[n]urils and Tiara[n]urils

Supramolecular delivery systems, such as cucurbit[n]urils (Q[n]), have many potential applications due to their ability to form noncovalent bonding interactions with molecular guests, especially in the field of drug delivery. In addition, the recently reported novel analogue tiara[n]urils (Tu[n]), which introduce amphiphilic properties, are potentially useful for drug delivery. Before reaching the drug delivery step, there is the rational drug design, which is a long journey that involves various chemical and biological aspects that need to be considered throughout the process. This thesis aims to extend the rational drug design journey to consider the delivery system through the macrocyclic hosts as a novel approach. It produces a series of novel drugs designed to work as dual therapeutic active anticancer and anti-leukotrienes (anti-15 LOX) drugs; the best biologically promising of the 11 drugs prepared were chosen for our further study. The design was based on selecting a marketed or known pharmacologically active compound, such as NSAIDs, where further considerations to the design include the drug delivery. This is an especially important feature to enhance solubility for pharmaceuticals. Our new approach began with synthesis to incorporate the desired features, testing for activity, then improving the delivery system, mainly the solubility of the best biologically promising designed drugs through the drug delivery vehicles. Following testing, computational chemistry studies were performed as a tool that bridges the gap between theoretical predictions and our practical applications. The study used different computational tools, such as Density functional theory, which was used to help explain the outcomes. Electrostatic potential maps provided a molecular-level understanding of complementary polarities, in conjunction with molecular orbital calculations.