Inhibitor of HIV-1 reverse

RH Smith Jr, WL Jorgensen, J Tirado-Rives, ML Lamb, PAJ Janssen, CJ Michejda, MBK Smith. Prediction of binding affinities for TIBO inhibitors of HIV-1 reverse transcriptase using Monte Carlo simulations m a linear response method. J Med Chem 41 5272-5286, 1998. 

Williams TM, Ciccarone TM, MacTough SC, Rooney CS, Balani SK, Con-dra JH, Emini EA, Goldman ME, Greenlee WJ, Kauffman LR, O Brien JA, Sardana VV, Schleif WA, Theoharides AD, Anderson PS. 5-Chloro-3-(phe-nylsulfonyl)indole-2-carboxamide a novel, non-nucleoside inhibitor of HIV-1 reverse transcriptase. J Med Chem 1993 36 1291-1294. 

Caranfa MJ, Breen AL, Bartus HR, Johnson RK, Hertzberg RP, Westley JW. The inophyllums, novel inhibitors of HIV-1 reverse transcriptase isolated from the Malaysian tree, Calophyllum inophyllum Linn. J Med Chem 1993 36 4131-4138. 

Saag MS, Emini EA, Laskin OL, Douglas J, Lapidus WI, Schleif WA, Whitley RJ, Hildebrand C, Byrnes VW, Kappes JC, Anderson KW, Massari FE, Shaw GM, the L-697,661 Working Group. A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. N Engl J Med 1993 329 1065-1072. 

Jorgensen, W. L. Ruiz-Caro, J. Tirado-Rives, J. Basavapathruni, A. Anderson, K. S. Hamilton, A. D. Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett. 2006,16, 663-667... 

Delavirdine (4.91), a selective inhibitor of HIV-1 reverse transcriptase, also contains an amido N-atom as part of a piperazine ring. In rats and monkeys, cleavage of the amide bond constituted only a minor pathway [56]. 

Tarrago-Litvak L et al. Inhibitors of HIV-1 reverse transcriptase and integrase Classical and emerging... 

Pyrimido[5,4-/]benzo[l,4]thiazepines 105 were alkylated by the Vorbruggen reaction at the pyrimidine nitrogen. The resulting uracil derivatives 106 are inhibitors of HIV-1 reverse transcriptase (Equation 10) <1995JME2145>. 

Chen et al. recently reported the stable ruthenium-oxo-oxalato cluster Na7[Ru4(p3-0)4(C204)g] (2) (Fig. lc) as a particularly potent inhibitor of HIV-1 reverse transcriptase (RT) with an IC50 value of 1.9 nM [17], Apparently, the polyanionic cluster mimics poly anionic nucleic acid in its binding to HIV-1 RT through electrostatic interactions. The cluster shows promising anti-HIV-1 activity without being cytotoxic. In contrast to many polyoxometallates, this cluster has been demonstrated to be stable under physiological conditions. 

Pyrroloquinolinequinone (213) (2,7,9-tricarboxy-l/7-pyrrolo[2,3-/]quinoline-4,5-dione, PQQ) (trivial name methoxatin) has been identified as a co-factor in many enzymes, including those that oxidize MeOH to HCHO in methylotrophic and autotrophic bacteria. Quinoproteins appear in mammalian systems as well, and methoxatin itself (213) has even been identified as an inhibitor of HIV-1 reverse transcriptase (for PQQ reviews, see <91MI 722-02, 95MI 722-02)). Interest in under-... 

These drugs are highly selective, noncompetitive inhibitors of HIV-1 reverse transcriptase. They do not interfere with the binding of primer, template, or nucleoside triphosphates. They have no effect on human DNA polymerases. Their major advantage is their lack of effect on the host blood-forming elements, and lack of cross-resistance with nucleoside reverse transcriptase inhibitors. 

Pyranocoumarins (C50 Phe pyran-2-one) include a variety of angular and linear compounds. A number of angular pyranocoumarins are spasmolytic and vasodilatory, notably the Ca2+ channel blocker visnadin. The inophyllums B and P from Calophyllum ionophyllum (Guttiferae) are inhibitors of HIV-1 reverse transcriptase. 

Benzodiazepines and 3//-1,5-benzodiazepines are important classes of compounds because of their interesting pharmacological properties. They show anticonvulsant, antianxiety, analgesic, sedative, antidepressive, hypnotic, antiinflammatory activity and also potent inhibitor of HIV-1 reverse transcriptase. Besides their biological relevance, benzodiazepines have also found application as dyes for acrylic fibers [163]. 

Figure 5.6 Complementarity between the major MFTA descriptor contributions to activity of the TIBO inhibitors of HIV-1 reverse transcriptase and the molecular properties of the biotarget protein a) atomic charge (Q) and electrostatic potential (EP) (b) atomic van der Waals radius (i ) and molecular surface (c) local lipophilicity (Lg) and molecular lipophilic potential (MLP) - see text for details.

The use of the Pathfinder descriptor for QSAR is exemplified here through application to two datasets taken from the literature (i) 31 steroids utilized in the original CoMFA study [3], since considered a benchmark for evaluating QSAR methods [4] (ii) 55 inhibitors of HIV-1 reverse transcriptase proposed by Chan and coworkers [5], interestingly this series could only be successfully correlated by means of a structure-based approach [6]. 

A, Anderson KS, Hamilton AD. Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg. 

Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase, dipyrido[2,3-/)]diazepinones, were prepared by J.R. Proudfoot and co-workers.These compounds are isomeric to the potent inhibitor nevirapine and available via the Smiles rearrangement of substrates that are intermediates used for the synthesis of nevarpine analogs. The deprotonated amide functionality in the rearrangement products displaces the chlorine at the 2-position to give the desired heterocycles in moderate to good yield. 

The total synthesis of the calophylium coumarin (-)-calanolide A was accomplished by D.C. Baker and co-workers. This compound attracted considerable attention because it is a potent inhibitor of HIV-1 reverse transcriptase. In order to introduce a formyl group at C8, a regioselective Vilsmeier reaction was employed on a coumarin lactone substrate. 

Gaudio, A.C. and Montanari, C.A. (2002) HEPT derivatives as nonnudeoside inhibitors of HIV-1 reverse transcriptase QSAR studies agree with the crystal structures. J. Comput. Aid. Mol Des., 16, 287-295. 

T Kovacs, L Parkanyi, I Pelczer, F Cervantes-Lee, KH Pannell, PF Torrence. Solid-state and solution conformation of 3 am ino-3 -dcoxy thymidine precursor to a noncompetitive inhibitor of HIV-1 reverse transcriptase. J Med Chem 34 2595-2600, 1991. 

Camarasa M-J, Velazquez S, San-Felix A et al (2006) Dimerization inhibitors of HIV-1 reverse transcriptase, protease and integrase a single mode of inhibition for the three HIV enzymes Antiviral Res 71 260-267... 

Non-competitive, allosteric inhibitors of adenosine kinase were reported by Butini et al.6S A biological screen of an in-house database of proprietary compounds identified pyrrolobenzoxazepines, representative of a class of nonnucleoside inhibitors of HIV-1 reverse transcriptase, with a unique T shape geometry as micromolar inhibitors of human adenosine kinase (e.g. compound... 

The chromeno-coumarin calanolide A, isolated from Calophyllum langiferum var. Austrocoriaceum, is nowadays in clinical trials as a nonnucleoside specific inhibitor of HIV-1 reverse transcriptase [64,65]. 

---