Rational Design, Synthesis, Anti-HIV-1 RT and Anti-microbial Activity of Novel 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-phenylpropanamide Derivatives

Author(s): Subhash Chander, Penta Ashok, Rajnish P. Singh, Prabhat N. Jha, Yong-Tang Zheng, Ping Wang, Sankaranarayanan Murugesan

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

Volume 14 , Issue 1 , 2016

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Graphical Abstract:


Background: AIDS continues to be a major public health issue worldwide. In 2014, an estimated 36.9 million people were living with HIV, in the same year, around 1.2 million people died due to AIDS-related illnesses. Due to global efforts particularly made in the last decade has reduced mortality rate due to AIDS and associated diseases. But still many people living with HIV/AIDS particularly in the low and middle income countries do not have access of anti-HIV drugs. Moreover, still there is no permanent cure of disease and rapid emergence of drug resistance by HIV towards the current available therapy further drive the need for the search of new potential anti- HIV drugs.

Methods: In the present study, fifteen novel 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-phenylpropanamide derivatives (5a-o) were designed as HIV-1 Reverse Transcriptase (RT) inhibitors, in-silico evaluated for drug likeness behaviour, synthesized and characterized. Compounds were evaluated in-vitro for inhibition of HIV-1 RT activity. Three compounds (5a, 5f and 5o) as representative of the series were evaluated for cytotoxicity studies on human T lymphocytes (C8166 cells). All the synthesized compounds were also evaluated for in-vitro antibacterial (E. coli, P. putida, S. aureus and B. cereus) and antifungal (C. albicans and A. niger) activity.

Results: All compounds (5a-o) possessed drug-likeness behavior based upon their in-silico predicted drug-likeness properties. Five compounds 5f, 5h, 5i, 5k and 5n exhibited more than 50% inhibition of HIV-1 RT, in which compound 5h showed highest inhibition (61%). Cytotoxicity studies of compounds 5a, 5f and 5o on T lymphocytes revealed that, all three exhibited CC50 >200 µg/ml. Four compounds 5f, 5i, 5j and 5n showed significant inhibition against the tested G(-) ve (E. coli and P. putida) bacterial strains while one compound 5f significantly inhibited the growth of all tested bacterial strains. Among the series, four compounds (5e, 5f, 5i and 5m) significantly inhibited the growth of A. niger, while compound 5m exhibited significant inhibition of both the tested fungal strains.

Conclusion: Titled compounds (5a-o) exhibited weak to significant inhibition of HIV-1 RT, particularly 5h. Four compounds showed significant anti-bacterial activity against the both tested G(-)ve bacterial strains, moreover compound 5f significantly inhibited the growth of all four tested bacterial strains. Four compounds significantly inhibited the growth of A. niger, in which compound 5m exhibited significant inhibition of both the tested fungal strains.

Keywords: AdmetSAR, antibacterial, antifungal, chloramphenicol, fluconazole, isoquinoline, resistance.

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Article Details

Year: 2016
Page: [63 - 73]
Pages: 11
DOI: 10.2174/2211352514666160125213608

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PDF: 125