Synthesis and Evaluation of 3-(1,3-dioxoisoindolin-2-yl)-N-substituted Phenyl Benzamide Analogues as HIV Integrase Strand Transfer Inhibitors

Author(s): Pankaj Wadhwa*, Priti Jain, Arpit Patel, Shantanu Shinde, Hemant R. Jadhav.

Journal Name: Anti-Infective Agents
Anti-Infective Agents in Medicinal Chemistry

Volume 17 , Issue 2 , 2019

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Abstract:

Background: A series of novel 3-(1,3-dioxoisoindolin-2-yl)-N-substituted phenyl benzamide derivatives was synthesized and tested in vitro against human immunodeficiency virus type-1 Integrase (HIV-1 IN).

Methods: Out of the 18 analogues, six (compounds 16c, 16h, 16i, 16m, 16n and 16r) showed significant inhibition of strand transfer by HIV-1 integrase. For these six compounds. IC50 was below 5.0 µM. In silico docking studies revealed that the presence of 2-phenyl isoindoline-1,3-dione motif was essential as it was found to interact with active site magnesium.

Results: To further confirm the results, cell-based HIV-1 and HIV-2 inhibitory assay was carried out.

Conclusion: These compounds possess structural features not seen in previously reported HIV-1 integrase inhibitors and thus can help further optimization of anti-HIV-1 integrase activity.

Keywords: HIV-1 integrase, strand transfer inhibitors, N-substituted phenyl benzamide, AIDS, IN inhibitors, docking studies.

[1]
Wadhwa, P.; Jain, P.; Jadhav, H.R.; Rudrawar, S. Quinoline, coumarin and other heterocyclic analogues based HIV-1 Integrase Inhibitors. Curr. Drug Discov. Technol., 2017.
[http://dx.doi.org/10.2174/1570163814666170531115452]
[2]
Wilen, C.B.; Tilton, J.C.; Doms, R.W. Molecular mechanisms of HIV entry. Adv. Exp. Med. Biol., 2012, 726, 223-242.
[3]
Prada, N.; Markowitz, M. Novel integrase inhibitors for HIV. Expert Opin. Investig. Drugs, 2010, 19, 1087-1098.
[4]
Yan, A.; Xuan, S.; Hu, X. Classification of active and weakly active ST inhibitors of HIV-1 integrase using a support vector machine. Comb. Chem. High Throughput Screen., 2012, 15, 792-805.
[5]
Dayam, R.; Neamati, N. Active site binding modes of the beta-diketoacids: A multi-active site approach in HIV-1 integrase inhibitor design. Bioorg. Med. Chem., 2004, 12, 6371-6381.
[6]
Li, Y.; Xuan, S.; Feng, Y.; Yan, A. Targeting HIV-1 integrase with strand transfer inhibitors. Drug Discov. Today, 2015, 20, 435-449.
[7]
Di Santo, R.; Costi, R.; Roux, A.; Artico, M.; Lavecchia, A.; Marinelli, L.; Novellino, E.; Palmisano, L.; Andreotti, M.; Amici, R.; Galluzzo, C.M.; Nencioni, L.; Palamara, A.T.; Pommier, Y.; Marchand, C. Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors: Design, synthesis, biological activities, and mechanism of action. J. Med. Chem., 2006, 49, 1939-1945.
[8]
Noguchi, T.; Fujimoto, H.; Sano, H.; Miyajima, A.; Miyachi, H.; Hashimoto, Y. Angiogenesis inhibitors derived from thalidomide. Bioorg. Med. Chem. Lett., 2005, 15, 5509-5513.
[9]
Bach, D.H.; Liu, J.Y.; Kim, W.K.; Hong, J.Y.; Park, S.H.; Kim, D.; Qin, S.N.; Luu, T.T.; Park, H.J.; Xu, Y.N.; Lee, S.K. Synthesis and biological activity of new phthalimides as potential anti-inflammatory agents. Bioorg. Med. Chem., 2017, 25, 3396-3405.
[10]
Davood, A.; Iman, M.; Pouriaiee, H.; Shafaroodi, H.; Akhbari, S.; Azimidoost, L.; Imani, E.; Rahmatpour, S. Novel derivatives of phthalimide with potent anticonvulsant activity in PTZ and MES seizure models. Iran. J. Basic Med. Sci., 2017, 20, 430-437.
[11]
Hu, S.; Yuan, L.; Yan, H.; Li, Z. Design, synthesis and biological evaluation of Lenalidomide derivatives as tumor angiogenesis inhibitor. Bioorg. Med. Chem. Lett., 2017, 27, 4075-4081.
[12]
Sharma, U.; Kumar, P.; Kumar, N.; Singh, B. Recent advances in the chemistry of phthalimide analogues and their therapeutic potential. Mini Rev. Med. Chem., 2010, 10, 678-704.
[13]
Nayab, P.S.; Irfan, M.; Abid, M.; Pulaganti, M.; Nagaraju, C.; Chitta, S.K. Rahisuddin. Experimental and molecular docking investigation on DNA interaction of N-substituted phthalimides: Antibacterial, antioxidant and hemolytic activities. Luminescence, 2017, 32, 298-308.
[14]
Verschueren, W.G.; Dierynck, I.; Amssoms, K.I.; Hu, L.; Boonants, P.M.; Pille, G.M.; Daeyaert, F.F.; Hertogs, K.; Surleraux, D.L.; Wigerinck, P.B. Design and optimization of tricyclic phtalimide analogues as novel inhibitors of HIV-1 integrase. J. Med. Chem., 2005, 48, 1930-1940.
[15]
Zhao, X.Z.; Semenova, E.A.; Vu, B.C.; Maddali, K.; Marchand, C.; Hughes, S.H.; Pommier, Y.; Burke, T.R., Jr 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one-based HIV-1 integrase inhibitors. J. Med. Chem., 2008, 51, 251-259.
[16]
Zhao, X.Z.; Maddali, K.; Vu, B.C.; Marchand, C.; Hughes, S.H.; Pommier, Y.; Burke, T.R., Jr Examination of halogen substituent effects on HIV-1 integrase inhibitors derived from 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-ones and 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones. Bioorg. Med. Chem. Lett., 2009, 19, 2714-2717.
[17]
Zhao, X.Z.; Maddali, K.; Metifiot, M.; Smith, S.J.; Vu, B.C.; Marchand, C.; Hughes, S.H.; Pommier, Y.; Burke, T.R., Jr Development of tricyclic hydroxy-1H-pyrrolopyridine-trione containing HIV-1 integrase inhibitors. Bioorg. Med. Chem. Lett., 2011, 21, 2986-2990.
[18]
Zhao, X.Z.; Maddali, K.; Metifiot, M.; Smith, S.J.; Vu, B.C.; Marchand, C.; Hughes, S.H.; Pommier, Y.; Burke, T.R., Jr Bicyclic hydroxy-1H-pyrrolopyridine-trione containing HIV-1 integrase inhibitors. Chem. Biol. Drug Des., 2012, 79, 157-165.
[19]
Goldgur, Y.; Craigie, R.; Cohen, G.H.; Fujiwara, T.; Yoshinaga, T.; Fujishita, T.; Sugimoto, H.; Endo, T. Murai, H.; Davies, D.R. Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: A platform for antiviral drug design. Proc. Natl. Acad. Sci. USA, 1999, 96, 13040-13043.
[20]
Debyser, Z.; Cherepanov, P.; Pluymers, W.; De Clercq, E. Assays for the evaluation of HIV-1 integrase inhibitors. Nucl. Methods and Proteo; Humana Press: Totowa, NJ, 2001, pp. 139-155.


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Article Details

VOLUME: 17
ISSUE: 2
Year: 2019
Page: [105 - 114]
Pages: 10
DOI: 10.2174/2211352516666181102121920

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