Formation of morpholine-acetamide derivatives as potent anti-tumor drug candidates: Pharmacological evaluation and molecular docking studies

Ahmed Sadiq Sheikh; Reem Altaf; Humaira Nadeem; Muhammad Tariq Khan; Babar Murtaza

doi:10.1016/j.heliyon.2023.e22183

Formation of morpholine-acetamide derivatives as potent anti-tumor drug candidates: Pharmacological evaluation and molecular docking studies

Heliyon. 2023 Nov 14;9(11):e22183. doi: 10.1016/j.heliyon.2023.e22183. eCollection 2023 Nov.

Authors

Ahmed Sadiq Sheikh¹, Reem Altaf², Humaira Nadeem¹, Muhammad Tariq Khan³, Babar Murtaza¹

Affiliations

¹ Department of Pharmaceutical Chemistry, Riphah Institute of Pharmaceutical Sciences, RIU, Islamabad, Pakistan.
² Department of Pharmacy, Iqra University, Islamabad, Pakistan.
³ Faculty of Pharmacy, CUST, Islamabad, Pakistan.

Abstract

Heterocyclic amines and acetamide derivatives are known for their chemotherapeutic potential. Hence, in the present study, morpholine was taken as a principal product and novel morpholine derivatives were designed, formulated, characterized, and screened for the mechanism of inhibition of carbonic anhydrase and their anticancer potential. In addition, in vitro inhibition of hypoxia-inducible factor-1 (HIF-1) protein was also investigated. Results revealed that compounds 1c, 1d, and 1h possessed significant inhibitory activities against carbonic anhydrase with IC₅₀ of 8.80, 11.13, and 8.12 μM, respectively. Interestingly, the carbonic anhydrase inhibitory activity of compound 1h was comparable with that of standard acetazolamide (IC₅₀ 7.51 μM). The compounds 1h and 1i significantly inhibited the proliferation of ovarian cancer cell line ID8 with IC₅₀ of 9.40, and 11.2 μM, respectively while the standard cisplatin exhibited an IC₅₀ 8.50 μM. In addition, compounds 1c, 1b, 1h and 1i also exhibited significant inhibitory effects on HIF-1α. In conclusion, we report first time the biological potential of morpholine based compounds against ovarian cancer and HIF-1α that may serve as lead molecules for drug discovery.

Keywords: Anti-tumor activity; Carbonic anhydrase inhibition; HIF-1α; Heterocyclic amines; MTT (3-[4,5-dimethylthiazole-2-yl]-2,5 diphenyl tetrazolium bromide) assay; Morpholine based compounds.