HIV protease, inhibition

M. Clare, R. A. Mueller, and K. Houseman, Effect of hydroxyl group configuration in hydroxyethlamine dipeptide isosteres on HIV protease inhibition, J. Med. Chem. 34 1222(1991). 

The work that paved the way toward enzymatic inhibition was published in the early 1990s by Wudl and coworkers (Schinazietal., 1993 Friedmanetal., 1993 Sijbesma et al., 1993) and since then studies regarding antiviral activity, mainly HIV-protease inhibition, have been carried out to find active compounds. Up to now, the most effective fullerene derivatives are the trans-2, -dimethy 1-bis-fulleropyrrolidin-ium salt (Fig. 1.4) (Marchesan et al., 2005) and the dendrofullerene reported by Hirsch (Schuster et al., 2000) both of them present an ECJ0 of 0.2pM. Also HIV reverse transcriptase can be inhibited by, -dimcthyl-bis-fulleropyrrolidinium salts (Mashino et al., 2005). The same compounds are also active against acetylcholine esterase (AChE), an enzyme that hydrolyzes a very important neurotransmitter. 

Nakamura E, Tokuyama H, Yamago S, Shiraki T, Sugiura Y (1996) Biological activity of water-Soluble fullerenes. Structural dependence of DNA cleavage, cytotoxicity, and enzyme inhibitory activities including HIV-Protease inhibition. Bull. Chem. Soc. Jpn. 69 2143-2151. 

Reduction of the carbonyl in the r >[CO-CH2-NH] link 7 (R1 = H) results in the (hy-droxy)ethyleneamino or r >[CH(OH)-CH2-NH] link 8 (R1 = H), which has proved to be a very potent analogue of the tetrahedral hydrated intermediate of the scissile amide bond. It has been widely used for the design of various inhibitors of HIV protease 141,142 14 154 and ACE, 155-157 and to synthesize angiotensin II, III, and IV analogues. 158,159 Indeed, the chirality of the hydroxylated carbon is critical for HIV protease inhibition, but separation of the epimers may be difficult. Therefore, the stereoselective synthesis from epoxides has been actively investigated. An example of a C-methylated tp[CMe(OH)-CH2-NH] link, obtained from an epoxide with chromatographic separation of the epimers, has also been described. 157 Most of the [(hydroxy)ethyleneamino] peptides have been prepared by solution procedures, but two examples of solid-phase synthesis have been reported. A theoretical study of the (hydroxy)ethyleneamino replacement for the amide bond has been carried out on a HIV protease inhibitor. 160 ... 

Beta-blocker H2 Blocker ACElnhib Antihistamine Antiretrovira lipid lowering SSRl PPl Antifungal Atypical neuroleptic Eknesis A2 antag Leukotriene antag HIV protease inhibit... 

Ghosh et al. [180] developed cycHc sulfolanes (55) as novel and high affinity P2 ligands for HIV protease inhibition. Gupta et al. [137] conducted detailed QSAR studies on this data and gave QSAR 65. 

Bisacchi et al. [193] studied BOC (t-butyloxycarbonyl) modified analogs of the C2 symmetric aminodiols (61) for HIV protease inhibition. The inhibitory... 

Boutton et al. [243] reported a genotype-dependent QSAR for HIV protease inhibition. A computational structure-based approach was used to predict the resistance of the HIVPI strain to Amprenavir (5) by calculating the... 

Sc(OTf)3 (4 mol%)-catalyzed addition of 1-trimethylsilyl nitropropanate to aryl and alkylimines was described [109]. The use of N-(4-methoxyphenyl)imines gave superior yields and/or diastereoselectivities of P-nitro amines in most cases (72-99% yield, antijsyn = 5/3-9/1). The products could be reduced to 1,2-diamines by samarium diiodide reduction, formation of the cyclic urea and cleavage of the 4-methoxyphenyl group with ceric ammonium nitrate (CAN). This methodology was later employed for the synthesis of pseudo-C2-symmetric triamines as candidates for human immunodeficiency virus (HIV) protease inhibition [110]. 

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