Two diverged series of water-soluble non-peptidic quinoline analogues were designed and synthesized by sequential attachment of piperazine and various amino acids to quinoline scaffold at first and second position using peptide coupling procedures. All synthesized compounds were subjected to the in-silico screening against HIV protease-1 and the cytotoxicity property of all synthesized compounds was examined on HCT116 cells. The compound, which has threonine and piperazine in sequence at quinoline second position found to have significant HIV protease inhibition property and demonstrated cytotoxicity IC50 value at 22.7±0.59 nM. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim