Synthesis, Biological Evaluation and Studies of Novel Pyrrolidine Derived Thiosemicarbazones As Dihydrofolate Reductase Inhibitors

Overview

Journal RSC Adv

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2024 Oct 9

PMID 39380649

Authors

Hina Aftab

Saeed Ullah

Ajmal Khan

Mariya Al-Rashida

Talha Islam

Abdulrahman Alshammari

Norah A Albekairi

Parham Taslimi

Ahmed Al-Harrasi

Zahid Shafiq

Saeed Alghamdi

Affiliations

Soon will be listed here.

Abstract

Dihydrofolate reductase (DHFR) is a crucial enzyme involved in folate metabolism and serves as a prime target for anticancer and antimicrobial therapies. In this study, a series of 4-pyrrolidine-based thiosemicarbazones were synthesized and evaluated for their DHFR inhibitory activity. The synthesis involved a multistep procedure starting from readily available starting materials, leading to the formation of diverse thiosemicarbazone 5(a-r) derivatives. These compounds were then subjected to assays to evaluate their inhibitory potential against DHFR enzyme. The synthesized compounds 5(a-r) exhibited potent inhibition with IC values in the range of 12.37 ± 0.48 μM to 54.10 ± 0.72 μM. Among all the derivatives 5d displayed highest inhibitory activity. Furthermore, molecular docking and ADME studies were performed to understand the binding interactions between the synthesized compounds and the active site of DHFR. The and data were correlated to identify compounds with promising inhibitory activity and favorable binding modes. This comprehensive study provides insights into the structure-activity relationships of 4-pyrrolidine-based thiosemicarbazones as DHFR inhibitors, offering potential candidates for further optimization towards the development of novel therapeutic agents.

References

Shehzad M, Hameed A, Al-Rashida M, Imran A, Uroos M, Asari A . Exploring antidiabetic potential of adamantyl-thiosemicarbazones via aldose reductase (ALR2) inhibition. Bioorg Chem. 2019; 92:103244. DOI: 10.1016/j.bioorg.2019.103244. View

Tasdemir D, Karakucuk-Iyidogan A, Ulasli M, Taskin-Tok T, Oruc-Emre E, Bayram H . Synthesis, molecular modeling, and biological evaluation of novel chiral thiosemicarbazone derivatives as potent anticancer agents. Chirality. 2014; 27(2):177-88. DOI: 10.1002/chir.22408. View

Wrobel A, Baradyn M, Ratkiewicz A, Drozdowska D . Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents. Int J Mol Sci. 2021; 22(7). PMC: 8037161. DOI: 10.3390/ijms22073685. View

Jiang X, Fielding L, Davis H, Carroll W, Lisic E, Deweese J . Inhibition of Topoisomerases by Metal Thiosemicarbazone Complexes. Int J Mol Sci. 2023; 24(15). PMC: 10419228. DOI: 10.3390/ijms241512010. View

Bilal Tufail M, Javed M, Ikram M, Mahnashi M, Alyami B, Alqahtani Y . Synthesis, pharmacological evaluation and Molecular modelling studies of pregnenolone derivatives as inhibitors of human dihydrofolate reductase. Steroids. 2021; 168:108801. DOI: 10.1016/j.steroids.2021.108801. View

Kalinowski D, Quach P, Richardson D . Thiosemicarbazones: the new wave in cancer treatment. Future Med Chem. 2011; 1(6):1143-51. DOI: 10.4155/fmc.09.80. View

Petri G, Raimondi M, Spano V, Holl R, Barraja P, Montalbano A . Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds. Top Curr Chem (Cham). 2021; 379(5):34. PMC: 8352847. DOI: 10.1007/s41061-021-00347-5. View

Hsieh Y, Skacel N, Bansal N, Scotto K, Banerjee D, Bertino J . Species-specific differences in translational regulation of dihydrofolate reductase. Mol Pharmacol. 2009; 76(4):723-33. PMC: 2769051. DOI: 10.1124/mol.109.055772. View

Capasso C, Supuran C . Sulfa and trimethoprim-like drugs - antimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors. J Enzyme Inhib Med Chem. 2013; 29(3):379-87. DOI: 10.3109/14756366.2013.787422. View

10.

Umamatheswari S, Balaji B, Ramanathan M, Kabilan S . Synthesis, stereochemistry, antimicrobial evaluation and QSAR studies of 2,6-diaryltetrahydropyran-4-one thiosemicarbazones. Eur J Med Chem. 2011; 46(4):1415-24. DOI: 10.1016/j.ejmech.2011.01.029. View

11.

Ragab A, Ammar Y, Ezzat A, Mahmoud A, Mohamed M, El-Tabl A . Synthesis, characterization, thermal properties, antimicrobial evaluation, ADMET study, and molecular docking simulation of new mono Cu (II) and Zn (II) complexes with 2-oxoindole derivatives. Comput Biol Med. 2022; 145:105473. DOI: 10.1016/j.compbiomed.2022.105473. View

12.

Singh P, Kaur M, Sachdeva S . Mechanism inspired development of rationally designed dihydrofolate reductase inhibitors as anticancer agents. J Med Chem. 2012; 55(14):6381-90. DOI: 10.1021/jm300644g. View

13.

Hassan N, Sabt A, El-Attar M, Ora M, Bekhit A, Amagase K . Modulating leishmanial pteridine metabolism machinery via some new coumarin-1,2,3-triazoles: Design, synthesis and computational studies. Eur J Med Chem. 2023; 253:115333. DOI: 10.1016/j.ejmech.2023.115333. View

14.

Ertas M, Sahin Z, Bulbul E, Bender C, Biltekin S, Berk B . Potent ribonucleotide reductase inhibitors: Thiazole-containing thiosemicarbazone derivatives. Arch Pharm (Weinheim). 2019; 352(11):e1900033. DOI: 10.1002/ardp.201900033. View

15.

Hassan G, El-Messery S, Al-Omary F, Al-Rashood S, Shabayek M, AbulFadl Y . Nonclassical antifolates, part 4. 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiols as a new class of DHFR inhibitors: synthesis, biological evaluation and molecular modeling study. Eur J Med Chem. 2013; 66:135-45. DOI: 10.1016/j.ejmech.2013.05.039. View

16.

Scaccaglia M, Pinelli S, Manini L, Ghezzi B, Nicastro M, Heinrich J . Gold(III) complexes with thiosemicarbazone ligands: insights into their cytotoxic effects on lung cancer cells. J Inorg Biochem. 2023; 251:112438. DOI: 10.1016/j.jinorgbio.2023.112438. View

17.

Raimondi M, Randazzo O, La Franca M, Barone G, Vignoni E, Rossi D . DHFR Inhibitors: Reading the Past for Discovering Novel Anticancer Agents. Molecules. 2019; 24(6). PMC: 6471984. DOI: 10.3390/molecules24061140. View

18.

Arooj M, Zahra M, Islam M, Ahmed N, Waseem A, Shafiq Z . Coumarin based thiosemicarbazones as effective chemosensors for fluoride ion detection. Spectrochim Acta A Mol Biomol Spectrosc. 2021; 261:120011. DOI: 10.1016/j.saa.2021.120011. View

19.

Tasleem M, Pelletier J, Sevigny J, Hussain Z, Khan A, Al-Harrasi A . Synthesis, in vitro, and in silico studies of morpholine-based thiosemicarbazones as ectonucleotide pyrophosphatase/phosphodiesterase-1 and -3 inhibitors. Int J Biol Macromol. 2024; 266(Pt 2):131068. DOI: 10.1016/j.ijbiomac.2024.131068. View

20.

Osman E, Emam S, Sonousi A, Kandil M, Abdou A, Hassan R . Design, synthesis, anticancer, and antibacterial evaluation of some quinazolinone-based derivatives as DHFR inhibitors. Drug Dev Res. 2023; 84(5):888-906. DOI: 10.1002/ddr.22060. View