Drug Design, In Silico-Profiling of New Pyrrole Derivatives: Promising Anticancer Agents Against Acute Myeloid Leukemia

zaid alsalamy; Ayad Kareem Khan; Mohammed Dheyaa Hamdi; Atheer Awad Mehde

doi:10.32947/ajps.v24i3.1063

Authors

zaid alsalamy Department of Pharmaceutical Chemistry, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
Ayad Kareem Khan Department of Pharmaceutical Chemistry, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
Mohammed Dheyaa Hamdi Department of Pharmaceutical Chemistry, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
Atheer Awad Mehde Sakarya University, Biomedical, Magnetic and Semiconductor Materials Application and Research Center (BIMAS-RC), 54187, Sakarya, Turkey

DOI:

https://doi.org/10.32947/ajps.v24i3.1063

Keywords:

in silico-profiling, pyrrole derivatives, Schiff bases, thiazolidinones, acute myeloid leukemia

Abstract

Molecular docking simulation and synthesis of five compounds of N2, N4-bis (2-(4-substituted phenyl)-4-oxothiazolidin-3-yl)-3,5-dimethyl-1H-pyrrole-2,4-dicarboxamide was carried out to evaluate their theoretical binding affinities, targeting acute myeloid leukemia (AML). The chemical structure of the molecules was accurately drawn using ChemDraw Professional 19.1 software.

The designed compounds were evaluated for their selectivity towards FLT3's ATP pocket (PDB ID:6JQR) in comparison with the reference ligand (Gilteritinib) by using GOLD suite from the Cambridge Crystallographic Data Centre (CCDC) software (Version 2021.2.0). All the designed compounds exhibited good binding energies with the receptor active pocket and had promising activity. Compounds 2E and 3E showed the highest PLP Fitness (83.30, 80.86 respectively) and it is higher than that of Gilteritinib (71.91). In-silico ADME and drug-likeness studies were performed by using the Swiss ADME server. The results showed that most of the designed compounds expected to be absorbed from the GIT. Compounds 2B-E have high expected GI absorption. All the investigated compounds have no predicted BBB penetration. Additionally, compounds 2A, 2C, 2D, and 3A are not a substrate to P-gps which may indicate a lower expected incidence of resistance by cancer cells in vitro studies. Finally, all of the investigated compounds are not considered to inhibit CYP1A2 enzyme, except for compounds 2A and 3D.

References

- Hassanpour SH, Dehghani M. Review of cancer from perspective of molecular. J Cancer Res Pract. 2017;4(4):127–9.

- Sinha T. Tumors: Benign and Malignant. Cancer Ther Oncol Int J. 2018;10(3).

- Kanar Muthanna Alawad, Monther Faisal Mahdi, Ayad M.R. Raauf. Molecular Docking study, and In vitro Evaluation of Antitumor Activity of Some New Isoxazoline and Pyrazoline Derivatives of Nabumetone against breast cancer cell line (MCF-7). Al Mustansiriyah J Pharm Sci. 2022 ;22(3) :24–34.

- Yao Y, Zhou Y, Liu L, Xu Y, Chen Q, Wang Y, et al. Nanoparticle-Based Drug Delivery in Cancer Therapy and Its Role in Overcoming Drug Resistance. Front Mol Biosci. 2020;7.

- Cheng Z, Li M, Dey R, Chen Y. Nanomaterials for cancer therapy: current progress and perspectives. J Hematol Oncol. 2021;14(1):85.

- Newell LF, Cook RJ. Advances in acute myeloid leukemia. BMJ. 2021; n2026.

- Kantarjian H, Kadia T, DiNardo C, Daver N, Borthakur G, Jabbour E, et al. Acute myeloid leukemia: current progress and future directions. Blood Cancer J. 2021;11(2):41.

- El-Gamal MI, Anbar HS, Yoo KH, Oh CH. FMS Kinase Inhibitors: Current Status and Future Prospects. Med Res Rev. 2013;33(3):599–636.

- Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33(2):299–312.

- Yamamoto Y. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97(8):2434–9.

- Daver N, Venugopal S, Ravandi F. FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm. Blood Cancer J. 2021 ;11(5) :104.

- Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3 -Mutated AML. N Engl J Med. 2019 ;381(18):1728–40.

- Kawase T, Nakazawa T, Eguchi T, Tsuzuki H, Ueno Y, Amano Y, et al. Effect of Fms-like tyrosine kinase 3 (FLT3) ligand (FL) on antitumor activity of gilteritinib, a FLT3 inhibitor, in mice xenografted with FL-overexpressing cells. Oncotarget. 2019;10(58):6111–23.

- Ramos P, Bentires-Alj M. Mechanism-based cancer therapy: resistance to therapy, therapy for resistance. Oncogene. 2015;34(28):3617–26.

- Lazo JS, Skoko JJ, Werner S, Mitasev B, Bakan A, Koizumi F, et al. Structurally Unique Inhibitors of Human Mitogen-Activated Protein Kinase Phosphatase-1 Identified in a Pyrrole Carboxamide Library. J Pharmacol Exp Ther. 2007;322(3):940–7.

- Bhosale J, Dabur R, Jadhav G, Bendre R. Facile Syntheses and Molecular-Docking of Novel Substituted 3,4-Dimethyl-1H-pyrrole-2-carboxamide/carbohydrazide Analogues with Antimicrobial and Antifungal Properties. Molecules. 2018 ;23(4):875.

- Ceramella J, Iacopetta D, Catalano A, Cirillo F, Lappano R, Sinicropi MS. A Review on the Antimicrobial Activity of Schiff Bases: Data Collection and Recent Studies. Antibiotics. 2022;11(2):191.

- Rahman RMA, Alharbi AS, Alshammari NA. Synthesis of Novel 4-Thiazolidinone and Bis-Thiazalidin-4-One Derivatives Derived from 4-Amino-Antipyrine and Evaluated as Inhibition of Purine Metabolism Enzymes by Bacteria. Int J Org Chem. 2019;09(02):85–95.

- Daud S, Abid O ur R, Sardar A, Shah BA, Rafiq M, Wadood A, et al. Design, synthesis, in vitro evaluation, and docking studies on ibuprofen derived 1,3,4-oxadiazole derivatives as dual α-glucosidase and urease inhibitors. Med Chem Res. 2022;31(2):316–36.

- Nafie MS, Boraei ATA. Exploration of novel VEGFR2 tyrosine kinase inhibitors via design and synthesis of new alkylated indolyl-triazole Schiff bases for targeting breast cancer. Bioorg Chem. 2022; 122:105708.

- Mahdi MF, Kadhim FAH. Design, Synthesis and Acute Anti-Inflammatory Evaluation of New Non-Steroidal Anti-Inflammatory Agents Having 4- Thiazolidinone Pharmacophore. J Nat Sci Res. 2015;5(6):21–9.

- Agarwal S, Mehrotra R. An Overview of Molecular Simulation. JSM Chem. 2016;4(2):1024–8.

- Pagadala NS, Syed K, Tuszynski J. Software for molecular docking: a review. Biophys Rev. 2017;9(2):91–102.

- Fowler S, Chen WLK, Duignan DB, Gupta A, Hariparsad N, Kenny JR, et al. Microphysiological systems for ADME-related applications: current status and recommendations for system development and characterization. Lab Chip. 2020;20(3):446–67.

- Allawi MM, Mahdi MF, Raauf AMR. Synthesis, anti-inflammatory, molecular docking and ADME studies of new derivatives of ketoprofen as cyclooxygenases inhibitor. Al Mustansiriyah J Pharm Sci. 2019;19(4):125–39.

- Daina A, Zoete V. A BOILED-Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules. ChemMedChem. 2016;11(11):1117–21.

- Mirzaei S, Gholami MH, Hashemi F, Zabolian A, Farahani MV, Hushmandi K, et al. Advances in understanding the role of P-gp in doxorubicin resistance: Molecular pathways, therapeutic strategies, and prospects. Drug Discov Today. 2022;27(2):436–55.

- Ahmed Juvale II, Abdul Hamid AA, Abd Halim KB, Che Has AT. P-glycoprotein: new insights into structure, physiological function, regulation and alterations in disease. Heliyon. 2022;8(6): e09777.