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, Inhaltsverzeichnis

Synlett 2025; 36(05): 522-530
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

^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

› Institutsangaben

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 and Notes
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23 BDS-002–BDS-005; General Procedure A solution of intermediate 10 (20 mg, 0.068 mmol. 1.0 equiv) in pyridine (1.0 mL) was stirred at r.t. and the appropriate sulfonyl chloride (1.5 equiv) was added (BDS-002: 2,5-dimethoxybenzene-1-sulfonyl chloride; BDS-003: 2,5-dichlorobenzene-1-sulfonyl chloride; BDS-004: 4-methoxybenzene-1-sulfonyl chloride; BDS-005: 4-fluorobenzene-1-sulfonyl chloride). The resulting mixture was stirred overnight at 90 °C until the reaction was complete (TLC and LCMS). The mixture was treated with 1 N aq HCl (25 mL) to remove the pyridine, and then extracted with EtOAc (2 × 25 mL). The organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure in a rotary evaporator to give a crude product that was purified by flash chromatography (silica gel, 20% EtOAc–hexane). N-{4-[(7-Chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}-2,5-dimethoxybenzenesulfonamide (BDS-002) Off-white solid; yield: 68%. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.96 (S, 1 H), 7.38 (d, J = 2.38 Hz, 1 H), 7.25 (s, 1 H), 7.18–6.90 (m, 4 H), 6.60 (s, 1 H), 4.01 (s, 3 H), 3.78 (s, 3 H), 2.53 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 161.7, 155.5, 153.5, 152.9, 150.2, 146.4 (d, J = 21 Hz, ¹³C–¹⁹F), 145.1, 136.1 (d, J = 21 Hz, ¹³C–¹⁹F), 126.9, 124.4, 121.3, 117.4 (d, J = 21 Hz, ¹³C–¹⁹F), 116.6, 115.8 (d, J = 21 Hz, ¹³C–¹⁹F), 114.1 (d, J = 21 Hz, ¹³C–¹⁹F), 113.3, 112.2, 110.6, 57.3, 56.2, 12.9. LCMS: m/z [M + H]⁺ (C₂₁H₁₉ClFN₄O₅S): 493.07.
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