Anti-HIV-active compounds

Our group modified the anti-HIV lead compounds BA (182) and dihydrobetulinic acid (186) to produce another series of compounds with substituents at C-3 and a free C-28 carboxylic acid. These 3-0-acyl derivatives (262-275) were obtained by treating the triterpenes with an acid anhydride and DMAP in pyridine or with an acid chloride in pyridine. The anti-HIV activities of active 3-O-acyl derivatives are listed in Table 9-11. Among them, 3-0-(3, 3 -dimethylsuccinyl)-betulinic acid (263, DSB, PA-457) and -dihydrobetulinic acid (268) both demonstrated extremely potent anti-HIV activity in acutely infected H9 lymphocytes, with EC50 values of <0.35 nM, and remarkable TI values of >20,000 and >14,000, respectively. In contrast, 262 and 267, the 2, 2 -dimethyl isomers, showed significantly lower anti-HIV activity. Compounds 264-266, 269, and 270 were 10-100-fold less active than 263 and 268. Compounds without a carboxylic acid in the C-3 side chain... 

Conocurvone - Prototype of a New Class of Anti-HIV Active Compounds ... 

The glycosidic bond stability of 2,6, and 8-substituted purine dideoxynucleosides was also examined by us. While substitutions at the 2 and 6 positions result in small to moderate effects on the stability of the glycosidic bond of these dideoxynucleosides, the most dramatic effect is seen with substitution at the 8-position (Table 1). For example, one of the anti-HIV active compounds synthesized in our program was 8-hydroxy ddA. It is resistant to hydrolysis even at pH 1 ... 

Part 2 lead optimization affording selective, orally bioavailable compounds with potent anti-HIV activity. Eioorg. Med. Chem. Lett. 2001, 11, 2741-2745. 

The HEPT and TIBO derivatives were discovered as the result of a systematic evaluation for anti-HIV activity in cell culture. They were later found to achieve their anti-HIV-1 activity through an interaction with the HIV-1 RT. In contrast, nevirapine, pyridinone, and BHAP emerged from a screening program for HIV-1 RT inhibitors. The anti-HIV-1 activity of these compounds was subsequently confirmed in cell culture. Like the HEPT and TIBO derivatives, the 2, 5 -bis-0-(tert-butyldimethylsilyl)-3 -spiro-5" -(4" -amino-1", 2" -oxathiole-2", 2" -dioxide)-pyrimidine (TS AO) derivatives (Fig. 9) [65,66] and a-anilinophenylacetamides (a-APA) (Fig. 10) [67] were discovered through the evaluation of their anti-HIV activity in cell culture. Subsequently, they were found to act as specific inhibitors of HIV-1 RT. 

The new heterocyclic system represented by compounds of type 147 (eg. R = Cl), and containing a bis-fused [l,3,4]thiadiazepine moiety, was prepared by cyclocondensation of 1-aminobenzimidazoIe-2-thione with 6-chloropyrimidine-5-carboxaldehydes. Some representatives of the system (e.g. 147, R = NMe2> showed anti-HIV activity <00SC3719>. 

A few nitrogen-substituted allenes themselves are known as biologically active compounds [154], For example, the 9-(4 -hydroxy-1, 2 -butadienyl)adenine (268a) was found to inhibit in vitro replication and cytopathic effects of human immunodeficiency viruses HIV-1 and HIV-2 [155], More recently, an increase in the anti-HIV activity in cell cultures using the adenallene phosphotriester derivative 268b was reported (Scheme 8.72) [156]. 

Interestingly some 1,2-dithiin compounds have been shown to possess antiviral activity, including anti-HIV activity, and their chemistry is an active area of research associated with that of diatomic sulfur S2 [30,31]. 

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