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. 2024 Oct 8;14(43):31409-31421.
doi: 10.1039/d4ra05071a. eCollection 2024 Oct 1.

Synthesis, in vitro biological evaluation and in silico studies of novel pyrrolidine derived thiosemicarbazones as dihydrofolate reductase inhibitors

Hina Aftab  1 , Saeed Ullah  2 , Ajmal Khan  2   3 , Mariya Al-Rashida  4 , Talha Islam  4 , Abdulrahman Alshammari  5 , Norah A Albekairi  5 , Parham Taslimi  6 , Ahmed Al-Harrasi  2 , Zahid Shafiq  1 , Saeed Alghamdi  7
Affiliations

Synthesis, in vitro biological evaluation and in silico studies of novel pyrrolidine derived thiosemicarbazones as dihydrofolate reductase inhibitors

Hina Aftab et al. RSC Adv. .

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 in vitro assays to evaluate their inhibitory potential against DHFR enzyme. The synthesized compounds 5(a-r) exhibited potent inhibition with IC50 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 in vitro and in silico 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.

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Conflict of interest statement

The authors have declared no conflict of interest.

Figures

Fig. 1
Fig. 1. Reported pyrrolidine and thiosemicarbazone based DHFR Inhibitors.
Scheme 1
Scheme 1. Synthetic route for the preparation of thiosemicarbazones.
Fig. 2
Fig. 2. Structure activity relationship of the synthesized thiosemicarbazones.
Fig. 3
Fig. 3. Overlap of docked conformations of hDHFR inhibitors 5a–r, NADPH is shown in black, the standard inhibitor drug methotrexate is shown in cyan color and the co-crystallized inhibitor is shown in blue.
Fig. 4
Fig. 4. 3D and 2D binding site interactions of most hDHFR inhibitor 5d.
Fig. 5
Fig. 5. RMSD graph of 5d-hDHFR protein ligand complex for 100 ns simulation run.
Fig. 6
Fig. 6. Protein RMSF graph of 5d complexed with hDHFR. Residues that interact with the ligand are shown in green vertical bars.
Fig. 7
Fig. 7. Bioavailability radar diagram for compound 5d showing favorable oral bioavailability profile.
See this image and copyright information in PMC

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