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Bioorganic & Medicinal Chemistry Letters 16 (2006) 4444–4449 Tri-substituted triazoles as potent non-nucleoside inhibitors Martha De La Rosa, Hong Woo Kim, Esmir Gunic, Cheryl Jenket, Uyen Boyle, Yung-hyo Koh, Ilia Korboukh, Matthew Allan, Weijian Zhang, Huanming Chen, Wen Xu, Shahul Nilar, Nanhua Yao, Robert Hamatake, Stanley A. Lang, Zhi Hong, Zhijun Zhang and Jean-Luc Girardet* Valeant Research & Development, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA Received 5 May 2006; revised 9 June 2006; accepted 12 June 2006 Abstract—A new series of 1,2,4-triazoles was synthesized and tested against several NNRTI-resistant HIV-1 isolates. Several ofthese compounds exhibited potent antiviral activities against efavirenz- and nevirapine-resistant viruses, containing K103Nand/or Y181C mutations or Y188L mutation. Triazoles were first synthesized from commercially available substituted phenylthio-semicarbazides, then from isothiocyanates, and later by condensing the desired substituted anilines with thiosemicarbazones.
Ó 2006 Elsevier Ltd. All rights reserved.
(NNRTIs) are key components of most current combi- nation therapies used to fight HIV-1 infectionsThree molecules that belong to this class of compounds have been approved by the American Food and Drug Admin- istration (FDA).Nevirapine was approved in 1996 and continues to be used in various regimens. Efavirenz was approved in 1998 and is considered to be the current gold standard for NNRTIs. Delavirdine, approved in 1997, is not widely used, probably due to its lack of effi- cacy and its poor pharmacokinetic properties.Because of the propensity of HIV to rapidly mutate, new agents with better activity profiles against mutant HIV-1 re- Scheme 1. Reagents and conditions: (a) N,N-dimethylacetamide We have discovered a new class of compounds that dimethylacetal, 100 °C; (b) K2CO3, DMF, rt; (c) chloroacetyl chloride, exhibit good antiviral efficacy against the wild type Nevirapine
Figure 1. Currently approved NNRTIs nevirapine, delavirdine, and efavirenz, and new substituted triazole 1 from our high-throughput screening of87,000 small molecules.
Keywords: Antiviral; HIV-1; NNRTI; Triazole; K103N; Y181C; Y188L.
* Corresponding author. Tel.: +1 714 545 0100 x4204; fax: +1 714 641 7222; e-mail: 0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.06.048 M. De La Rosa et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4444–4449 (WT) enzyme and against the double mutant K103N- Y181C that arises from the use of the three currently approved NNRTIs.Compound 1 () was discov- ered by screening a library of 87,000 compounds using a cell-based assay. This first compound showed moderate activity against viruses carrying WT or K103N-Y181C HIV-1 RT. Compound 1 was also active in an enzymatic assay against the purified WT HIV-1 RT.A compre- hensive literature search showed that SAR compounds could be accessed through a 3-step synthesis startingfrom Scheme 2. Reagents and conditions: (a) RCOOEt, EtOH, MeONa, reflux or CF3COOH, reflux; (b) K2CO3, DMF, rt.
Values are means of multiple experiments (nd, not determined); EFV, efavirenz.
M. De La Rosa et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4444–4449 Values are means of multiple experiments (nd, not determined); EFV, efavirenz.
substitutions at the 4-position of the triazole ring as well Ring cyclization of the desired thiosemicarbazides 2a–i corresponding triazoles 3a–i in good yields. Linkers 6a–r were obtained by condensing anilines 5a–r with 11c-q: X=CH
chloroacetyl chloride in dichloromethane, with or with- out the presence of diisopropylethylamine. The two fragments were reacted together in dimethylformamide in the presence of potassium carbonate to give com- pounds 4a–i and 7a–r in excellent yield after precipita- tion (adding water to the reaction mixture induced precipitation of the pure product in most cases) or Various substitutions at the 5-position of the triazole were also explored through cyclization of a thiosemicarbazide with various esters or with trifluoroacetic ). The resulting triazoles 8a–k were condensed with thelinkers 6a following the same protocol as described Scheme 3. Reagents and conditions: (a) HNO3, 0 °C; (b) H2, Pd–C or earlier, to yield compounds 9a–k. The antiviral activities Raney-Ni, ethanol, rt; (c) thiosemicarbazide, DMF, rt; (d) DMF, of these series against wt and mutant HIV-1 were evaluat- reflux 3 h; (e) NaOH 1 N, 40 °C; (f) N,N-dimethylacetamide dimethy- ed using a cell-based assay system employing VSV-G- lacetal, 100 °C; (g) K2CO3, DMF, rt.
M. De La Rosa et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4444–4449 Values are means of multiple experiments; EFV, efavirenz.
pseudotyped pNL4-3.Luc.R-E reporter virus and HeLa- JC53 cell(). Compounds 4b–d and 4h,i showed (EC50 > 2lM); however, switching the N-4 substitution a very strong inhibition of the wild type virus (sub-nano- from a phenyl group to a naphthyl group, as shown with molar range), along with an improved inhibition of the compound 15b, gave us submicromolar potency against double mutant K103N-Y181C when compared to com- Y188L virus (). The need to explore more substi- pound 1. The presence of an ortho or para R1 substituent tuted aryls at the N-4 position of the triazole led us to improved activities against both viruses, with the biggest design a more convergent and straightforward synthesis effect being observed when R1 was in para position. We Instead of the classical scheme involving a decided to select R1 as a para methyl to study the SAR thiosemicarbazide intermediate, we found that the thio- at R2. Compounds 7a, b, g, j, k, m, r showed the strongest semicarbazone could be condensed and cyclized HIV-1 inhibition, and shared the presence of an ortho hal- in two convenient steps in one pot with an aniline, an ogen substitution on the aniline. A secondary substitution 8-aminoquinoline or a naphthylamine to give 14a–q.
was accepted in most cases, as seen with compounds 7a, j, Yields were only fair (50–60%), but the convenience of n, o. Para substituents like methyl and methyl carboxylate the reaction allowed us to synthesize many triazoles in showed similar good activity, while trifluoromethoxy and isopropyl exhibited a reduced activity. The range of sub-stitutions allowed at the position 5 of our triazole proved One of the hurdles in the synthesis of various substituted to be narrow as seen in compounds 9a–k; only methyl, naphthalenes was the regioselectivity of the nitration. In ethyl, and trifluoromethyl showed good activity on the some cases, we obtained two or more isomers that had wild type virus, and methyl was the only substitution to be separated and identified based on their NMR pat- exhibiting sub-micromolar potency against K103N- tern. Reduction of the nitro compounds was accom- Y181C mutant virus in this first series of compounds.
plished using either Raney-nickel or palladium oncarbon catalysts under 1–3 atm of hydrogen. A few We later added another efavirenz-resistant mutant virus substituted naphthylamines were commercially available to our testing panel (Y188L), and we noticed that none and were condensed directly with the thiosemicarbazone 13. The presence of two fused rings at N-4 dramatically M. De La Rosa et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4444–4449 improved the antiviral activities against Y188L ). While N-4 phenyl-substituted triazole compoundswere poorly active on Y188L mutants, most naphtha-lene compounds inhibited viral growth at submicromo-lar level, and compounds 16c, f, h, i, k exhibiteddouble-digit nanomolar activity on both mutant viruses.
Since the Y188L mutant virus was more resistant to ourseries of compounds than the double mutant K103N-Y181C, we decided to test our newer compounds onlyagainst WT and Y188L viruses (see Scheme 6. Reagents and conditions: (a) CSCl2; (b) hydrazine; (c) The trend observed with R1 substituents in the previous trifluoroacetic acid; (d) 24, K2CO3, DMF, rt.
set of compounds proved to be applicable to naphtha-lene substitutions, with the most active compounds hav- The linker was condensed with the previously obtained ing a para substitution. These results motivated us to triazoles 14a–f,j,k to yield compounds 25a–h. This new expand our SAR to more bicyclic ring systems, and we linker brought several folds improvement in potency turned toward the synthesis of various substituted quin- against the Y188L resistant mutant when compared to any other available R2-substituted anilines. Quinolines cyclized with acetaldehyde in the presence of hydrochlo- 19a–f were cyclized following a procedure described ric acid to give nitroquinolines 18a–g, which were subse- above to yield triazoles 26a–f, and were condensed with quently reduced to give 8-aminoquinolines 19a–g. Also, linker 24 to give compounds 27a–f. We also prepared a from 3,5-dimethylaniline 20, we built the 2,5,7-trimeth- few 5-trifluoromethyl-substituted triazoles by condens- ylquinoline 19h following a slightly longer chemical ing thiosemicarbazides 28a–j with trifluoroacetic acid, route, involving a nitration step with potassium nitrite followed by a ring cyclization, to yield compounds in sulfuric acid, followed by reduction with sodium dithionite. We also synthesized the linker 24 ) in 3 steps after noticing some similarities with another Except for compounds 30b and 30f, the presence of the 5-trifluoromethyl replacing the 5-methyl-substitution onthe triazole improved the antiviral activity against theY188L mutant. Another observation was that when bearing the same R1 substituents, naphthalene com- pounds were more active than the corresponding quino- lines, as exemplified by the couples 25a–b, 30a–h, and to a lesser extent 25h–27b. Compounds 25f,h, and 30e, j exhibited single-digit nanomolar activity against the Y188L mutant, with no cytotoxicity. This was a 10-fold improvement when compared to efavirenz tested side- by-side. More interestingly, in the case of compounds Scheme 4. Reagents and conditions: (a) H2O, HCl, acetaldehyde, 30e and 30j, there was only a 4-fold loss of potency rt-70 °C; (b) H2, Pd–C or Raney-Ni, ethanol, rt; (c) potassium nitrate, against Y188L as compared to WT. The loss of potency sulfuric acid, 0 °C to rt; (d) sodium dithionite, ethanol, H2O, reflux.
for efavirenz was about 180-fold. This improved activityprofile against an efavirenz-resistant virus could proveextremely valuable, and warrants further studies on more efavirenz-resistant viruses.A number of im- proved compounds from this triazole scaffold are cur- rently being considered for clinical evaluation. The results of these studies will be presented at a later time.
Thanks to Robert Selliah and Haoyun An for some stimulating discussions, to our analytical group for 25b-h: X=CH
numerous sample purifications and analyses, and to Heli Walker and Jae Hoon Shim for the construction of Scheme 5. Reagents and conditions: (a) NH3, THF; (b) HCl, EtOH/ 1. De Clercq, E. J. Clin. Virol. 2004, 30, 115.
water; (c) chloroacetyl chloride, CH2Cl2; (d) K2CO3, DMF, rt; (e) 2. Zhang, Z.; Hamatake, R.; Hong, Z. Antiviral Chem.
DMF, reflux 3 h; (f) NaOH 1 N, 40 °C.
M. De La Rosa et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4444–4449 3. De Clercq, E. Chem. Biodiv. 2004, 1, 44.
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14. Results to be part of future publications.


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