Approaches to the synthesis of a novel, anti-HIV active integrase inhibitor

Abstract

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.

Figure 1

A molecular modeling picture of the HIV intasome (pdb code 3OYA) depicting the interaction of compound 1 (green) with both the viral enzyme [α-helix (red), β-sheets (blue) and connecting strands (yellow)] and viral DNA (orange-red, light blue and gray atom colors). Compound 1 interacts through chelation with two magnesium ions (purple spheres) in the integrase active site. Other interactions involve integrase amino acid residues Tyr 143, Pro 145 and Asp 116. There is also a pi stacking interaction of one phenyl ring of compound 1 with the cytosine ring of deoxycytidine 16 of viral DNA. All of these interactions within the active-site pocket combine to block the ability of the HIV intasome to incorporate viral DNA into human DNA.

Scheme 1

Synthesis of intermediate 5a and 5b

Scheme 2

Two possible synthetic pathways to key intermediate 7

Scheme 3

Conversion of intermediate 7 to target compound 1