TIBO analogues

Parker, K. A. Coburn, C. A. Regioselectivity in intramolecular nucleophilic aromatic substitution. Synthesis of the potent anti HIV-18-halo TIBO analogues. J. Org. Chem. 1992, 57, 97— 100. 

The sites at which anti-HIV drugs may. in principle, act, are dealt with in detail under a main heading (see ANTIVIRAL agents). In summary, currently, of the drugs actually in use, a number are reverse transcriptase (enzyme) inhibitors (RTIs). Examples of nucleoside RTIs include zidovudine, didanosine and zalcitabine. Some non-nucleoside RTIs include foscarnet sodium, nevirapine, carbovir and TIBO analogues (some of these are at trial stage only). 

The 181 Tyr — Cys mutation, which is responsible for resistance to most NNRTIs, has been found to suppress the 215 mutation (Thr — Phe/ Tyr), which is responsible for resistance to AZT [94], and, vice versa, the 181 Tyr — Cys mutation can be suppressed by AZT, which thus means that the mutations at positions 181 and 215 counteract each other. Yet other mutations have proved to counteract each other 236 Pro — Leu vs 138 Glu —> Lys, and, as mentioned, 215 Thr > Phe/Tyr vs 184 Met > Val, and 215 Thr — Phe/Tyr vs 74 Leu > Val [47]. Based on the resistance mutations that counteract each other, combinations of different drugs could be envisaged—namely, combinations of AZT with either TIBO, a-APA, HEPT, nevirapine, or pyridinone—and these two drug combinations could be extended to three- or four-drug combinations by the addition of another ddN analogue (such as 3TC) and/or another NNRTI (such as BHAP or TSAO). 

Buckheit RW Jr., White EL, Germany-Decker J, Allen LB, Ross LJ, Shannon WM, et al. Cell-based and biochemical analysis of the anti-HIV activity of combinations of 3 -azido-3 -deoxythymidine and analogues of TIBO. Antiviral Chem Chemother 1994 5 35 12. 

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. 

Different cyclization reactions of ort o-ami no-substituted benzothiazepinones 54 lead to tricyclic derivatives 55, containing imidazole (X = CR), 1,2,3-triazole (X = N), or tetrahydropyrazine (X = CH2CH2) rings (Equation 3). These compounds are structural analogues of the anti-HIV product thiobenzimidazolone (TIBO) <1999EJM701>. 

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. 

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