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Synthesis, In Vitro Anti-HIV Activity, Cytotoxicity, and Computational Studies of Some New Steroids and Their Pyrazoline and Oxime Analogues

Abstract

There is an urgent need for the design and development of new and safer drugs for the treatment of HIV infection, active against the currently resistant viral strains by development of new non-nucleoside reverse transcriptase inhibitors (NNRTIs). A series of pregnenolone analogues, 3-((aryl)-1-(5-pregnen-3β-ol-17-yl)prop-2-en-1-ones, were synthesized. Further, treatment of 3-((4-bromo-, 4-trifluoromethyl, or 4-methylphenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-ones with thiosemicarbazide in ethanolic KOH or hydrazine hydrate in HOAc gave 5-(4-bromo-, 4-trifluoromethyl, or 4-methylphenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline, respectively. Analogously, treatment of 3-((4-bromophenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one with hydroxylamine afforded the Z/E isomers of 3-(4-bromophenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one oxime. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 3-(thiophene-2-yl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline were the most active in inhibiting HIV-1 and HIV-2 with IC50 = 60.5 μM (SI > 2, against HIV-2 and SI < I against HIV-1), and > 0.29 μM (SI < I), respectively, suggesting to be new leads in the development of antiviral agents. QSAR of 3-((aryl)-1-(5-pregnen-3β-ol-17-yl)prop-2-en-1-ones and 5-(substituted phenyl)-3-(5-preg-5-3β-ol-17-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamides has been studied. The conformational analysis of 5-(4-trifluoromethylphenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline-1-carbothioamide and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline as well as the molecular docking study of the latter compound have been investigated.

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ACKNOWLEDGMENTS

W. Al-Masoudi would like to thank College of Verterinary, Basrah University, Iraq, for the sabbatical leave. We thank Miss A. Friemel of the Chemistry, Department, Konstanz University, Germany, for the 2D NMR experiments.

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Correspondence to Najim A. Al-Masoudi.

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Corresonding author: e-mail: najim.al-masoudi@gmx.de (web: www.al-masoudi.de).

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Wasfi A. Al-Masoudi, Al-Masoudi, N.A., Saeed, B.A. et al. Synthesis, In Vitro Anti-HIV Activity, Cytotoxicity, and Computational Studies of Some New Steroids and Their Pyrazoline and Oxime Analogues. Russ J Bioorg Chem 46, 822–836 (2020). https://doi.org/10.1134/S1068162020050039

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  • DOI: https://doi.org/10.1134/S1068162020050039

Keywords:

  • anti-HIV activity
  • α-unsaturated ketones
  • cytotoxicity
  • molecular docking study
  • QSAR
  • pregnenolone