De-novo design, synthesis and evaluation of novel 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as HIV-1 reverse transcriptase inhibitors

Chemistry Central Journal

Subhash Chander¹  Penta Ashok¹  Anupam Singh¹  Sankaranarayanan Murugesan¹ 

[1] Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani 333031, Rajasthan, India

关键词: Resistance;    Glide;    NNRTI;    Docking;    HIV-1 RT;    Tetrahydroisoquinoline;   

Others  :  1213780
DOI  :  10.1186/s13065-015-0111-6

 received in 2015-05-29, accepted in 2015-06-02,  发布年份 2015

【 摘 要 】

Background

Acquired Immune Deficiency Syndrome (AIDS) is the advanced stage of infection caused by Human Immunodeficiency Virus (HIV). HIV/AIDS had a great impact on society, both as an illness and as a source of discrimination. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are structurally diverse group of compounds which binds to Reverse Transcriptase (RT) enzyme of HIV. Like other anti-HIV drugs, long-term clinical effectiveness of approved NNRTIs has been hampered due to the rapid development of drug resistance. So, there is an urgent need to discover the NNRTIs, which can be effective against the drug sensitive as well as drug resistant strains of HIV-1 RT.

Results

Two series of novel thirty, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline analogues (5a-o) and (8a-o) were designed and synthesized as inhibitor of HIV-1 reverse transcriptase. All the synthesized compounds were characterized by infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, mass spectroscopy and evaluated for in-vitro RT inhibitory activity. Among the tested compounds, eighteen compounds exhibited more than 50 % inhibition at tested 100 μM concentration, in which two compounds 8h and 8l showed promising inhibition (74.82 and 72.58 %) respectively. The preliminary structure–activity relationship (SAR) of the test compounds and docking studies of the two significantly active compounds 8h and 8l were performed to examine their putative binding with HIV-RT. Predicted physiochemical parameters of the synthesized compounds were within the acceptable range of drugable properties.

Conclusion

The results obtained from this investigation revealed that, the synthesized compounds (5a-o) and (8a-o) showed moderate to promising HIV-1 RT inhibition activity. The overall SAR studies can help in identification of further lead as well as in designing of newer potential inhibitor of HIV-1 RT.

【 授权许可】

   
2015 Chander et al.

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【 参考文献 】

• [1]Flexner C. HIV drug development: the next 25 years. Nat Rev Drug Discovery. 2007; 6:959-66.
• [2]Maggiolo F, Airoldi M, Kleinloog HD, Callegaro A, Ravasio V, Arici C et al.. Effect of adherence to HAART on virologic outcome and on the selection of resistance-conferring mutations in NNRTI- or PI-treated patients. HIV Clin Trials. 2007; 8:282-92.
• [3]Liu XH, Zhu J, Zhou AN, Song BA, Zhu HL, Bhadury PS et al.. Synthesis, structure and antibacterial activity of new 2-(1-(2-(substituted-phenyl)-5-methyloxazol-4-yl)-3-(2-substitued-phenyl)-4,5-dihydro-1H-pyrazol-5-yl)-7-substitued-1,2,3,4-tetrahydroisoquinoline derivatives. Bioorg Med Chem Lett. 2009; 17:1207-13.
• [4]Scott JD, Williams RM. Chemistry and biology of the tetrahydroisoquinoline antitumor antibiotics. Chem Rev. 2002; 102:1669-730.
• [5]Boustie J, Stigliani JL, Montanha J, Amoros M, Payard M, Girre L. Antipoliovirus structure-activity relationships of some aporphine alkaloids. J Nat Prod. 1998; 61:480-4.
• [6]Cheng P, Huang N, Jiang ZY, Zhang Q, Zheng YT et al.. 1-aryl tetrahydroisoquinoline analogues as active anti-HIV agents in vitro. Bioorg Med Chem Lett. 2008; 18:2475-8.
• [7]Minor DL, Wyrick SD, Charifson PS, Watts VJ, Nichols DE, Mailman RB. Synthesis and molecular modeling of 1-phenyl-1,2,3,4-tetrahydroisoquinolines and related 5,6,8,9-tetrahydro-13BH-dibenzo[a, h]quinolizines as D1 dopamine antagonists. J Med Chem. 1994; 37:4317-28.
• [8]Pham VC, Ma J, Thomas SJ, Xu Z, Hecht SM. Alkaloids from Alangium javanicum and Alangium grisolleoides that mediate Cu2+-dependent DNA strand scission. J Nat Prod. 2005; 68:1147-52.
• [9]Boyd MR, Hallock YF, Cardellina JH, Manfredi KP, Blunt JW, McMahon JB et al.. Anti-HIV michellamines from Ancistrocladus korupensis. J Med Chem. 1994; 37:1740-5.
• [10]El S, Khalid A. Natural products as antiviral agents Stud. Nat Prod Chem. 2000; 24:473-572.
• [11]Hajos G, Riedl Z, Molnar J, Szabo D. Non-nucleoside reverse transcriptase inhibitors. Drug Future. 2000; 25:47-62.
• [12]Kashiwada Y, Aoshima A, Ikeshiro Y, Chen YP, Furukawa H, Itoigawa M et al.. Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera and structure-activity correlations with related alkaloids. Bioorg Med Chem. 2005; 13:443-8.
• [13]Kennedy-Smith JJ, Arora N, Billedeau JR, Fretland J, Hang JQ, Heilek GM et al.. Synthesis and biological activity of new pyridone diaryl ether non-nucleoside inhibitors of HIV-1 reverse transcriptase. Med Chem Comm. 2010; 1:79-83.
• [14]Zhan P, Chen W, Li Z, Li X, Chen X, Tian Y et al.. Discovery of novel 2-(3-(2-chlorophenyl)pyrazin-2-ylthio)-N-arylacetamides as potent HIV-1 inhibitors using a structure-based bioisosterism approach. Bioorg Med Chem Lett. 2012; 20:6795-802.
• [15]Yang S, Pannecouque C, Daelemans D et al.. Molecular design, synthesis and biological evaluation of BP-O-DAPY and O-DAPY derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors. Eur J Med Chem. 2013; 65:134-43.
• [16]version 5.9. Schrödinger, LLC, New York; 2013.
• [17]Friesner RA, Murphy RB, Repasky MP et al.. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem. 2006; 49:6177-96.
• [18]Jorgensen WL, Maxwell DS, Tirado RJ. Development and testing of the OPLS all-atom force field on conformational energetics of organic liquids. J Am Chem Soc. 1996; 118:11225-36.
• [19]version 2.6. Schrödinger, LLC, New York; 2013.
• [20]version 3.7. Schrödinger, LLC, New York; 2013.
• [21]Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G et al.. admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model. 2012; 52:3099-105.