_1732901625 20241129173345000 Editor editor.jddt@gmail.com Universal Journal of Pharmaceutical Research Universal Journal of Pharmaceutical Research Univ J Pharm Res 2456-8058 2831-5235 11 15 2024 Koffi Charles Kouman https://orcid.org/0009-0003-8591-4804 Affiba Florance Kouassi https://orcid.org/0009-0008-7629-8575 Yves Kily Hervé Fagnidi https://orcid.org/0000-0001-7198-4068 Issouf Fofana https://orcid.org/0009-0004-9000-9224 Koffi N’Guessan Placide Gabin Allangba https://orcid.org/0009-0001-0320-7168 Mélalie Kéïtaépouse Guego https://orcid.org/0009-0004-5113-9712 Eugene Megnassan https://orcid.org/0000-0003-1505-5277 Background: During the previous decade, Anti-tuberculosis therapies were confronted with drug-resistant strains. We report here virtual design and evaluation of novel piperazine (PPZ) as inhibitors of InhA-Mt endowed with favorable predicted pharmacokinetic profiles. Method: Three-dimensional (3D) models of InhA-PPZx complexes were prepared by in situ modifications of the crystal structure of InhA-PPZ1 (Protein Data Bank (PDB) entry code: 1P44), the reference compound of a training set of 12 PPZs with known experimental inhibitory potencies (IC50exp). First, in the search for active conformation of the PPZ 1-12, we built a gas phase quantitative structure-activity relationships (QSAR) model, linearly correlating the computed enthalpy of the InhA-PPZ complex formation and the pIC50exp. Finally, the VCL filtered by Lipinski’s rule-of-five was screened by the PH4 model and the potencies of the new PPZ analogs obtained were evaluated with the initial QSAR and their pharmacokinetic profile was evaluated. Results: The VCL of 310,500 PPZs s was filtered down to 19,044 analogs by the Lipinski’s rule. The five-point PH4 screening retained 50 new potent PPZs with predicted inhibitory potencies IC50pre up to 100-times better than that of PPZ1 (IC50exp=160 nM). Predicted pharmacokinetic profile of the new analogs showed enhanced cell membrane permeability, side effect and high human oral absorption compared to current anti-tuberculosis candidates Conclusions: Combining molecular modeling and PH4 in virtual screening of the VL resulted in the proposed novel potent antituberculotic agent candidates with favorable pharmacokinetic profiles.              Peer Review History: Received 21 July 2024;   Reviewed 13 September 2024; Accepted 20 October; Available online 15 November 2024 Academic Editor: Dr. Asia Selman Abdullah, Pharmacy institute, University of Basrah, Iraq, asia_abdullah65@yahoo.com Average Peer review marks at initial stage: 6.0/10 Average Peer review marks at publication stage: 7.5/10 Reviewers: Antonio José de Jesus Evangelista, Federal University of Ceará, UFC, Brazil, tony_biomed@hotmail.com Asmaa Ahmed Mohamed Ahmed Khalifa, Pharos University, Alexandria, Egypt, asmaa.khalifa@pua.edu.eg 11 15 2024 http://creativecommons.org/licenses/by-nc/4.0 10.22270/ujpr.v9i5.1216 https://ujpronline.com/index.php/journal/article/view/1216 https://ujpronline.com/index.php/journal/article/download/1216/1750 https://ujpronline.com/index.php/journal/article/download/1216/1750 https://ujpronline.com/index.php/journal/article/download/1216/1751 https://ujpronline.com/index.php/journal/article/download/1216/1752