Synthesis, Characterization, and Biological Applications of Tetramethylpiperidinyl Triazolopyridazine Derivatives

Srinivasa Reddy Keesara; Ratnasekhar Bolla; Hanumantharayappa Bharathkumar; Sai Balaji Andugulapati; Sreedhar Gundekari; Mohan Varkolu

doi:10.1055/a-2384-6983

Synlett, Table of Contents

Synlett 2025; 36(05): 459-463
DOI: 10.1055/a-2384-6983

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Synthesis, Characterization, and Biological Applications of Tetramethylpiperidinyl Triazolopyridazine Derivatives

Srinivasa Reddy Keesara

^aDepartment of Chemistry, Koneru Lakshmaiah Education Foundation, RVS Nagar, Aziz Nagar (PO), Moinabad Road, Hyderabad, Telangana, 500075, India

,

Ratnasekhar Bolla

^aDepartment of Chemistry, Koneru Lakshmaiah Education Foundation, RVS Nagar, Aziz Nagar (PO), Moinabad Road, Hyderabad, Telangana, 500075, India

,

Hanumantharayappa Bharathkumar

^bDepartment of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India-500007, India

,

Sai Balaji Andugulapati

^cDepartment of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India

,

Sreedhar Gundekari

,

Mohan Varkolu∗

^aDepartment of Chemistry, Koneru Lakshmaiah Education Foundation, RVS Nagar, Aziz Nagar (PO), Moinabad Road, Hyderabad, Telangana, 500075, India

› Author Affiliations

Abstract

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Abstract

We have synthesized a series of tetramethylpiperidinyl triazolopyridazine derivatives and screened the molecules for their biological activity against a cancer (NCI-H460) cell line. Among the tested molecules, 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol significantly inhibited cell growth with an IC₅₀ value of 5.2 μM. We hope that this study will help in the development of better candidates for the treatment of lung cancer.

Key words

triazolopyridazines - lung cancer - medicinal chemistry - biological activity - anticancer drugs

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References

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29 Products 9a–d; General Procedure A mixture of compound 7 (1.0 equiv), the appropriate boronic acid 8a–d (1.2 equiv), and K₂CO₃ (2.0 equiv) in 10:4 1,4-dioxane–H₂O was degassed with N₂ for 15 min at r.t., then Pd(dppf)Cl₂ (0.15 equiv) was added at r.t. under N₂. The mixture was stirred for 6 h at 75–80 °C under N₂ until 7 was completely consumed (TLC), then cooled to r.t. The reaction was quenched with ice-water and the mixture was extracted with EtOAc. The organic phase was separated, and the aqueous layer was extracted with EtOAc. The combined organic phase was dried (Na₂SO₄) and concentrated, and the crude product was purified by column chromatography. 2-[3-(2,2,6,6-Tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol (9a) Off-white solid; yield: 0.80 g (53%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.22 (s, 1 H), 8.23 (d, J = 7.2 Hz, 1 H), 8.12 (s, 2 H), 7.71 (s, 1 H), 7.54 (d, J = 7.4 Hz, 1 H), 5.63 (m, 1 H), 2.20 (m, 2 H), 1.99 (m, 2 H), 1.35 (s, 6 H), 1.15 (s, 6 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 157.3 (C5), 153.6 (C21), 148.6 (C23), 141.2 (C29), 137.8 (C30), 137.3 (C2), 132.0 (C1), 121.7 (C25), 117.4 (C6, C24), 109.9 (C7), 106.9 (C22), 56.9 (C12 & C14), 51.9 (C10), 30.2 (C11 & C15), 24.7 (C16–C19). LC/MS: m/z = 419 [M + H]⁺.

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