An estimated 38 million people globally are currently living with human immunodeficiency virus (HIV-1). While HIV-1 can be effectively treated with antiretroviral therapy (ART), the efficacy of ART is challenged by its cost, regular access to health care, and the development of viral resistance. Methods to both prevent and eradicate HIV-1 infection are thus desperately needed. One potential method for eradication is CD4-mimetic compounds (CD4mcs). Typically, the HIV-1 envelope glycoprotein (Env) trimer on the virion surface interacts with the host receptors, CD4 and CCR5/CXCR4, to mediate virus entry into the target cell. CD4mcs comprise small organic molecules that bind in the highly conserved CD4-binding site of Envgp120 and prematurely induce inactivating Env conformational changes. By inducing more “open,” antibody-susceptible Env conformations, CD4mcs also sensitize HIV-1 virions to neutralization by antibodies and infected cells to antibody-dependent cellular cytotoxicity (ADCC). In this thesis, the development of more potent CD4mcs is discussed. In the first portion of this thesis, the modification of the C(5) side-chain of a lead CD4mc, BNM-III-170 is discussed. By replacing this side-chain with differentially substituted pyrrolidine, piperidine, and piperazine ring systems, guided by structural and computational analyses, we found that the 5-position of BNM-III-170 is remarkably tolerant of a variety of ring sizes and substitutions, both in regard to antiviral activity and sensitization to humoral responses. Crystallographic analyses of representative analogs from the pyrrolidine series revealed the potential for 5-substituents to hydrogen bond with gp120 Env residue Thr 283. The second portion of this thesis comprises the design and synthesis of butyl chain derivatives at the indane ring 3-position of our lead CD4-mimetic compound BNM-III-170, which branch into previously unexplored chemical space on the Env surface. Biological evaluation revealed that members of this series of CD4-mimetic compounds are able to inhibit HIV-1 viral entry into target cells more potently and with greater breadth compared to BNM-III-170. Crystallographic analysis revealed a novel hydrogen bonding interaction between His 105 and a primary hydroxyl group on the butyl side chain. In the final portion of this thesis, we report the design, synthesis and evaluation of novel CD4mcs based on an indoline scaffold. Compared with our current lead indane scaffold CD4mc, BNM-III-170, several indoline CD4mcs exhibit increased potency and breadth against HIV-1 variants from different geographic clades. Viruses that were selected for resistance to the lead indane CD4mc, BNM-III-170, are susceptible to inhibition by the indoline CD4mcs. The indoline CD4mcs also potently sensitize HIV-1-infected cells to ADCC mediated by plasma from HIV-1-infected individuals. Co-crystal structures indicate that the indoline CD4mcs make favorable contacts with the vestibule of the CD4-binding pocket on gp120. The rational design of indoline CD4mcs thus holds promise for further improvements in antiviral activity, potentially contributing to efforts to treat and prevent HIV-1 infection.