Design and synthesis of potent macrocyclic HIV-1 protease inhibitors and non-nucleoside dengue virus mRNA methyltransferase inhibitors

Linah N Rusere, Purdue University

Abstract

The first part of this thesis describes a novel class of macrocyclic HIV-1 protease inhibitors. A series of macrocyclic inhibitors containing aromatic P2 ligand have been designed, synthesized and evaluated. The inhibitors have been designed by incorporating 16-18 membered macrocyclic rings between the aromatic P2 ligand, and a tyrosine P1 ligand attached to (hydroxyethylamino)sulfonamide isostere resembling the P1'-P 2' ligand in TMC-126. The macrocyclic compounds were more potent than the corresponding acyclic compounds. All macrocyclic compounds and their acyclic precursors exhibited high enzyme inhibitory potency, displaying K i values between 0.2 nM and 45 nM. Ring-closing metathesis using Grubbs 1st generation catalyst furnished the cis/trans unsaturated macrocycles. The synthesis of the aromatic P2 ligand was carried out using a 1,6-electrocyclization reaction. The isosteres containing two stereocenters were conveniently prepared through a series of stereo- and regioselective transformations including copper cyanide catalyzed SN 2 epoxide opening, Sharpless asymmetric epoxidation, and regioselective epoxide opening with TMSN3 in the presence of Ti(O-iPr) 4. A series of slightly modified 15- and 16-membered macrocyclic inhibitors containing meta-substituted aromatic P1 ligand have also been prepared. The inhibitors displayed high enzyme inhibitory potency with Ki values between 0.05 nM and 2.26 nM. Among these was also a macrocycle containing a 3-hydroxysalicylic acid P2 ligand, which exhibited comparable potency. The second part of this thesis describes the synthesis of a novel class of methyltransferase inhibitors. N-alkyl substituted diaminoquinoline ureas were synthesized and examined for N-7 methylation inhibition in dengue virus methyltransferase-catalyzed mRNA cap formation. This series of inhibitors was derived from a lead identified by high throughput screening. All compounds showed high potency, displaying IC50 values as low as 0.2 &mgr;M. The urea-containing inhibitors were formed by coupling their respective diaminoquinoline monomers using triphosgene. A series of novel squaramide analogs of the urea-based inhibitors were also synthesized. These inhibitors were relatively less potent than the corresponding urea compounds. Adenine containing urea compounds were also prepared. However, these compounds did not show any significant methyltransferase inhibitory activity.

Degree

Ph.D.

Advisors

Ghosh, Purdue University.

Subject Area

Chemistry|Organic chemistry

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