TIBO derivatives

The first lead compounds for non-nucleoside reverse transcriptase (RT) inhibitors (NNRTl) were discovered about 15 years ago (Pauwels et al. 1990 Merluzzi et al. 1990 Goldman et al. 1991 De Clercq 1993 Riibsamen-Waigmann et al. 1997). Since then they have become an important ingredient of the dmg combination schemes that are currently used in the treatment of human immunodeficiency virus type 1 (HlV-1) infections. Starting from the HEPT and TIBO derivatives, numerous classes of compounds have been described as NNRTIs. Four compounds (nevirapine, delavirdine, efavirenz and etravirine) have so far been approved for clinical use and several others are the subject of clinical trials (Balzarini 2004 Stellbrink 2007). 

The identification of the HIV-1-specific non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a separate class of HIV inhibitors was heralded by the discovery of the tetrahydroimidazo[4,5,1 -// .][ 1,4]benzo-diazepin-2(l //)-onc and -thione (TIBO) derivatives (Fig. 7) [58,59] and 1 -(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) derivatives (Fig. 8) [60,61]. The first TIBO derivatives (R82150, R82913) were the first NNRTIs [58] postulated to act as inhibitors of HIV-1 RT [59], For the HEPT derivatives it became evident that they also interact specifically with HIV-1 RT after a number of derivatives (i.e., E-EPU, E-EBU, and E-EBU-dM) had been synthesized that were more active than HEPT itself [62,63]. Following HEPT and TIBO, several other compounds, i.e., nevirapine, pyridinone, and bis(heteroaryl)piperazine (BHAP), were... 

Figure 7 Tetrahydroimidazo[4,S,1 -jk] [1,4]benzodiazepin-2(1 H)-one (TIBO) derivatives (A) R82913 and (B) R86183 (with a chlorine substituted in the 9- or 8-position, respectively).

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. 

H, Janssen MAC, De Clercq E, Janssen PAJ. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature... 

De Vreese K, Debyser Z, Vandamme A-M, Pauwels R, Desmyter J, De Clercq E, Anne J. Resistance of human immunodeficiency virus type 1 reverse transcriptase to TIBO derivatives induced by site-directed mutagenesis. Virology 1992 188 900-904. 

Pauwels R, Andries K, Debyser Z, Kukla MJ, Schols D, Breslin HJ, et al. New TIBO derivatives are potent inhibitors of HIV-1 replication and are synergistic with 2, 3 -dideoxynucleoside analogues. Antimicrob Agents Chemother 1994 38 2863-2870. 

Pauwels R, Andries K, Desmyter J, Schols D, Kukla MJ, Breslin HJ, Raeymaeckers A, Van Gelder J, Woestenborghs R, Heykants J, Schellekens K, Janssen MAC, De Clercq E, Janssen PAJ (1990) Potent and Selective Inhibition of HIV-1 Replication in Vitro by a Novel Series of TIBO Derivatives. Nature 343 470... 

Zhou, Z., Madura, J.D. 3D QSAR Analysis of HIV-1 RT Nonnucleoside Inhibitors, TIBO Derivatives Based on Docking Conformation and Alignment. /. Chem. Inf Comput. Sci. 2004, 44, 2167-2178. 

As an example, let us consider the MFTA model of the HIV-1 reverse transcriptase inhibition by the tetrahydroimidazobenzodiazepinone (TIBO) derivatives. The model is based on the atomic charge Q, atomic van der Waals radius R and group lipophilicity Lg as the local descriptors (V=73, Np=5, i = 0.887, g = 0.686). Figure 5.5 shows the molecular supergraph with the superimposed structure of one training set compound. 

Molecular supergraph for a series of tetrahydroimidazobenzodiazepinone (TIBO) derivatives with superimposed structure of a representative training set compound. 

Huuskonen, J.J. (2001) QSAR modeling with the electrotopological state TIBO derivatives./. Chem. Inf. Comput. Sci., 41, 425-429. 

Sardana, S. and Madan, A.K (2002b) Predicting anti-HIV activity of TIBO derivatives a computational approach using a novel topological descriptor. 

MM-PBSA in Reproducing the Binding Free Energies to HIV-1 RT of TIBO Derivatives and Predicting the Binding Mode to HIV-1 RT of Efavirenz by Docking and MM-PBSA. 

Table 15 indicates the CWk for the calculation of DCWgao (vk, °EC t). It was reported [65] that the general interaction properties function approach (GIPF), which relies on quantum chemical parameters, was used for developing four-variable QSAR for the anti-HIV-1 potencies. However, the statistic obtained with this technique was R = 0.9300, 5 = 0.597 on the TIBO derivatives, and R = 0.9390, 5 = 0.404 on the HEPT derivatives. In other words, the results are practically equivalent. 

When the inhibition of HIV-1 RT by E-EBU-dM was further analyzed with varying concentrations of substrate and compound, double-reciprocal plots showed that this compound inhibits competitively with respect to dlTP and noncompetitively with respect to dGTP (data not shown). The ATm of HIV-1 RT for dTTP and dGTP was 27 and 7.7 pM, respectively. The Ki of the enzyme for E-EBU-dM with dTTP as substrate was 0.42 pM. Some benzodiazepine (TIBO) derivatives (47)50 reported recendy behave quite similarly to HEPT derivatives. Considering their common specificity for HIV-1, the HEPT and TIBO derivatives might work through a similar mechanism of action. However, the TIBO derivatives apparently differ from the HEPT analogues in that they do not act as competitive inhibitors of HIV-1 RT with respect to dTTP. 

Mandal, A. S., Roy, K. (2009). Predictive QSAR modeling of HIV reverse transcriptase irihibitor TIBO derivatives. Eur. J. Med. Chem. 44,1509-1524. 

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