Structure-Based Design of Novel HIV Protease Inhibitors: Carboxamide-Containing 4-Hydroxycoumarins and 4-Hydroxy-2-pyrones as Potent Nonpeptidic Inhibitors

Abstract

The low oral bioavailability and rapid biliary excretion of peptide-derived HIV protease inhibitors have limited their utility as potential therapeutic agents. Our broad screening program to discover nonpeptidic HIV protease inhibitors had previously identified compound II (phenprocoumon, K(i) = 1 muM) as a lead template. Crystal structures of HIV protease complexes containing the peptide-derived inhibitor I (1-(naphthoxyacetyl)-L-histidyl-5(S)-amino-6-cyclohexyl-3 (R),4(R)-dihydroxy-2(R)-isopropylhexanoyl-L-isoleucine N-(2-pyridylmethyl)amide) and nonpeptidic inhibitors, such as phenprocoumon (compound II), provided a rational basis for the structure-based design of more active analogues. This investigation reports on the important finding of a carboxamide functionally appropriately added to the 4-hydroxycoumarin and the 4-hydroxy-2-pyrone templates which resulted in a new promising series of nonpeptidic HIV protease inhibitors with improved enzyme-binding affinity. The most active diastereomer of the carboxamide-containing compound XXIV inhibited HIV-1 protease with a K(i) value of 0.0014 muM. This research provides a new design direction for the discovery of more potent HIV protease inhibitors as potential therapeutic agents for the treatment of HIV infection.

Synthesis, Spectroscopy and Electrochemistry of New 3-(5-Aryl-4,5-Dihydro-1H-Pyrazol-3-yl)-4-Hydroxy-2H-Chromene-2-One 4, 5 as a Novel Class of Potential Antibacterial and Antioxidant Derivatives

“…The remaining aromatic protons of the aromatic aldehydes and the four protons of the coumarin moiety appeared as a multiplet in the region δ 7.25 -8.08. 13 C-NMR spectra as well as by NOESY and HMBC 2D-NMR experiments to elucidate their structures and assign completely the structural network of both protons and carbons. The spectral data were in accordance with the proposed structures (see experimental section).…”

“…The structure of 4d was finally elucidated through the analysis of the 1 H, 13 C HMBC spectrum, which correlates the protons at δ 4.78 ppm with C 5' (δ 55.05 ppm) and C 2' (δ 153.3 ppm). The aromatic protons correlate with C 5' (δ 55, 05 ppm).…”

“…A large number of structurally novel coumarin derivatives have been reported to show substantial cytotoxic and anti-HIV activity both in vitro and in vivo [12,13]. A variety of synthetic coumarins have unique action mechanisms referring to the different stages of HIV replication [14].…”

TheFDAApprovedHIV‐1 Protease Inhibitors for Treatment ofHIV/AIDS

“…32) as a lead nonpeptide HIV inhibitor from a broad screening of a Pharmacia and Upjohn compound library [144]. Subsequent structural modifications revealed that replacement of the 4-hydroxycoumarin ring with a 4-hydroxypyrone and incorporation of substituted sulfonamides at the meta position of the phenyl side chain (see Fig.…”

An Improved Synthesis of 4-Chlorocoumarin-3-sulfonyl Chloride and Its Reactions with Different Bidentate Nucleophiles to Give Pyrido[1',2':2,3]- and Thiazino[3',2':2,3]-1,2,4-Thiadiazino[6,5-c]Benzopyran-6-one 7,7-Dioxides

“…Those derivatives have shown a remarkably broad spectrum of pharmacological and physiological activities and they are used as anticoagulant [4][5][6], antibacterial [7,8], antiviral [9,10], antitumor [11][12][13][14], bactericidal [15], fungicidal [16], and anti-inflammatory agents [17]. Also, in recent times there are references to derivatives with anti-HIV activity [18][19][20][21].…”