Synlett
DOI: 10.1055/a-2360-6586
letter

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
a   Department of Chemistry, Bharatiya Vidya Bhavan College, Chowpatty, Mumbai University, Mumbai, 400 007, India
b   Integral Biosciences Pvt Ltd, Drug Discovery Biotech, Delhi NCR-Noida, 201306, India
,
Meenakshi Meenakshi
b   Integral Biosciences Pvt Ltd, Drug Discovery Biotech, Delhi NCR-Noida, 201306, India
,
Yogesh Murti
c   Institute of Pharmaceutical Research, GLA University, Mathura 281406, India
,
Madhav Shivaji Mane
d   CSIR National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan Pune 411008, India
,
Sarvesh Kumar Pandey
e   Department of Chemistry, Deen Dayal Upadhyaya Gorakhpur University, Gorakhpur, Uttar Pradesh 273009, India
,
Shriya Mahajan
f   Centre of Research Impact and Outcome, Chitkara University, Rajpura 140417, Punjab, India
,
Pramod Rawat
g   Graphic Era (Deemed to be University), Clement Town, Dehradun 248002, India
h   Graphic Era Hill University, Clement Town, Dehradun 248002, India
,
Harsimrat Kandhari
i   Chitkara Centre for Research and Development, Chitkara University, Himachal Pradesh, 174103, India
,
Kapil Kumar Goel
j   Department of Pharmaceutical Sciences, Gurukul Kangri (Deemed to be University), Haridwar, India
,
k   GITAM School of Pharmacy, GITAM (Deemed to be) University, Hyderabad, 502329, India
,
S. V. Rathod
a   Department of Chemistry, Bharatiya Vidya Bhavan College, Chowpatty, Mumbai University, Mumbai, 400 007, India
› Author Affiliations


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.

Supporting Information



Publication History

Received: 23 April 2024

Accepted after revision: 04 July 2024

Accepted Manuscript online:
04 July 2024

Article published online:
05 August 2024

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