Development of New N-{4-[(7-Chloro-5-methylpyrrolo[2,1-f] [1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide Analogues: Exploring Anticancer Potential through MerTK Inhibition

Balaji Dashrath Sathe; Meenakshi Meenakshi; Yogesh Murti; Madhav Shivaji Mane; Sarvesh Kumar Pandey; Shriya Mahajan; Pramod Rawat; Harsimrat Kandhari; Kapil Kumar Goel; Ashish Ranjan Dwivedi; S. V. Rathod

doi:10.1055/a-2360-6586

Synlett, Table of Contents

Synlett 2025; 36(05): 522-530
DOI: 10.1055/a-2360-6586

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Development of New N-{4-[(7-Chloro-5-methylpyrrolo[2,1-f] [1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide Analogues: Exploring Anticancer Potential through MerTK Inhibition

Authors

Balaji Dashrath Sathe

^aDepartment of Chemistry, Bharatiya Vidya Bhavan College, Chowpatty, Mumbai University, Mumbai, 400 007, India

^bIntegral Biosciences Pvt Ltd, Drug Discovery Biotech, Delhi NCR-Noida, 201306, India
Meenakshi Meenakshi

^bIntegral Biosciences Pvt Ltd, Drug Discovery Biotech, Delhi NCR-Noida, 201306, India
Yogesh Murti

^cInstitute of Pharmaceutical Research, GLA University, Mathura 281406, India
Madhav Shivaji Mane

^dCSIR National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan Pune 411008, India
Sarvesh Kumar Pandey

^eDepartment of Chemistry, Deen Dayal Upadhyaya Gorakhpur University, Gorakhpur, Uttar Pradesh 273009, India
Shriya Mahajan

^fCentre of Research Impact and Outcome, Chitkara University, Rajpura 140417, Punjab, India
Pramod Rawat

^gGraphic Era (Deemed to be University), Clement Town, Dehradun 248002, India

^hGraphic Era Hill University, Clement Town, Dehradun 248002, India
Harsimrat Kandhari

ⁱChitkara Centre for Research and Development, Chitkara University, Himachal Pradesh, 174103, India
Kapil Kumar Goel

^jDepartment of Pharmaceutical Sciences, Gurukul Kangri (Deemed to be University), Haridwar, India
Ashish Ranjan Dwivedi ∗

^kGITAM School of Pharmacy, GITAM (Deemed to be) University, Hyderabad, 502329, India
S. V. Rathod∗

^aDepartment of Chemistry, Bharatiya Vidya Bhavan College, Chowpatty, Mumbai University, Mumbai, 400 007, India

Abstract

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Abstract

Mer proto-oncogene tyrosine-protein kinase (MerTK), a part of the TAM (TYRO3, AXL, and MerTK) family, is directly correlated with metastasis and various types of cancers. The inhibition of this receptor is a promising strategy for more-effective chemotherapy. Considering the pharmacophoric features of the active domain of MerTK and the structural characteristics of the investigational drug BMS794833, we designed five new N-{4-[(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide analogues. In cytotoxicity studies, one of the analogues displayed a significantly higher cytotoxicity than cisplatin. It showed IC₅₀ values of 2.09, 1.96, and 3.08 μM against A549, MCF-7, and MDA-MB-231 cancer cell lines, respectively. In drug metabolism and pharmacokinetic studies, it was the most stable analogue and displayed a moderate MerTK inhibitory potential. Molecular-docking studies were performed to corroborate the MerTK inhibition, and the same analogue achieved the most significant docking score (–12.33 kcal/mol). Docking interactions demonstrated that the imine and amine group of the 3-chloropyridine moiety of BMS794833 formed hydrogen bonds with the main chain of the ATP pocket residue Met674, while the oxygen atoms of the 4-oxo-1,4-dihydropyridine-3-carboxamide moiety established hydrogen bonds with the Lys619 and Asp741 amino acid residues of the allosteric pocket of MerTK protein. These promising results provide evidence that the N-{4-[(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide pharmacophore can give potential insights into the development of new MerTK inhibitors.

Key words

cancer chemotherapeutics - pyrrolotriazines - sulfonamides - metabolic studies - kinase inhibitors

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References

References and Notes
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