Worldwide research efforts in drug discovery involving HIV integrase have produced only one compound, raltegravir, that has been approved for clinical use in HIV/AIDS. As resistance, toxicity and drug-drug interactions are recurring issues with all classes of anti-HIV drugs, the discovery of novel integrase inhibitors remains a significant scientific challenge. We have designed a lead HIV-1 strand transfer (ST) inhibitor (IC50 70 nM), strategically assembled on a pyridinone scaffold. A focused structure-activity investigation of this parent compound led to a significantly more potent ST inhibitor, 2 (IC50 6 ± 3 nM). Compound 2 exhibits good stability in pooled human liver microsomes. It also displays a notably favorable profile with respect to key human cytochrome P450 (CYP) isozymes and human UDP glucuronosyl transferases (UGTs). The prodrug of inhibitor 2, i.e., compound 10, was found to possess remarkable anti-HIV-1 activity in cell culture (EC50 9 ± 4 nM, CC50 135 ± 7 μM, therapeutic index = 15,000).

Claisen condensation, the key step in constructing the pharmacophore of aryl beta-diketo acids (DKA) as integrase inhibitors, fails in certain cases of highly electron-deficient heterocycles such as purines. A general synthetic strategy to assemble the DKA motif on the purine scaffold has been accomplished. The synthetic sequence entails a palladium-catalyzed cross-coupling, a C-acylation involving a tandem addition/elimination reaction, and a novel ferric ion-catalyzed selective hydrolysis of an enolic ether in the presence of a carboxylic acid ester.

The novel dinucleotide 5'-phosphate, [(L,D)-pIsodApdC], discovered in our laboratory, is a strong inhibitor of HIV-1 integrase for both the 3'-processing and the strand transfer steps. The rationale used in this molecular design was that residues immediately upstream of the dinucleotide cleavage site in the 3'-processing step might provide critical recognition/binding sites on integrase. The rationale for the second type of inhibitors was based on the elimination products (linear and cyclic dinucleotides) of 3'-processing. However, while the linear dinucleotide 5'-phosphate (pdGpdT) was active, its cyclic counterpart was inactive against both wild-type and mutant HIV integrase.

Multi-drug resistant tuberculosis (MDR-TB) is emerging as a serious global health problem, which has been elevated through co-infection involving HIV and MDR-Mtb. The discovery of new compounds with anti-MDR TB efficacy and favorable metabolism profiles is an important scientific challenge. Using computational biology and ligand docking data, we have conceived a multifunctional molecule, 2, as a potential anti-MDR TB agent. This compound was produced through a multi-step synthesis. It exhibited significant in vitro activity against MDR-TB (MIC 1.56 μg/mL) and its half-life (t1/2) in human liver microsomes was 14.4 h. The metabolic profiles of compound 2 with respect to human cytochrome P450 (CYP) and uridine 5′-diphospho-glucuronosyltransferase (UGT) isozymes were favorable. Compound 2 also had relatively low in vitro cytotoxicity in uninfected macrophages. It displayed synergistic behavior against MDR-TB in combination with PA-824. Interestingly, compound 2 also displayed in vitro anti-HIV activity.

The novel HIV-1 integrase inhibitor 1, discovered in our laboratory, exhibits potent anti-HIV activity against a diverse set of HIV-1 isolates and also against HIV-2 and SIV. In addition, this compound displays low cellular cytotoxicity and possesses a favorable in vitro drug interaction profile with respect to isozymes of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT). However, the total synthesis of this significant HIV integrase inhibitor has not been reported. This contribution describes an optimized, reproducible, multi-step, synthetic route to inhibitor 1. The yield for the separate steps averaged about 80%. The methodologies utilized in the synthesis were, among others, a palladium-catalyzed cross-coupling reaction, a crossed-Claisen condensation, and a hydrazino amide synthesis step. Successful alternative synthetic methodologies for some of the steps are also described.