Recent Developments of 1,3,4-Thiadiazole Compounds as Anticancer Agents

Abstract

The World Health Organization has recently underlined the increasing global burden of cancer, with a particularly alarming impact on underserved populations. In recent years, 1,3,4-thiadiazole has emerged as a versatile pharmacophore to obtain bioactive compounds. The pharmacological properties of this ring are primarily attributed to its role as a bioisostere of pyrimidine, the core structure of three nucleic bases. This structural feature endows 1,3,4-thiadiazole derivatives with the ability to interfere with DNA replication processes. Additionally, the mesoionic behavior of this heterocycle gives it important properties, such as the ability to cross biological membranes and interact with target proteins. Noteworthy, in analogy to the other sulfur heterocycles, the presence of C-S σ* orbitals, conferring small regions of low electron density on the sulfur atom, makes interaction with the target easier. This review focuses on the most promising anticancer agents with 1,3,4-thiadiazole structure reported in the past five years, providing information that may be useful to medicinal chemists who intend to develop new anticancer derivatives.

Keywords: 1,3,4-thiadiazoles; anticancer agents; breast cancer; pancreatic ductal adenocarcinoma; sulfur-containing heterocycles.

Scheme 3

Synthesis of derivatives 14a–c. Reagents and conditions: (i) CH₃COONa, acetone, chloroacetyl chloride, 0 °C, 1 h; (ii) dry benzene, suitable piperazine, TEA, reflux, 16–20 h.

Scheme 9

Synthesis of thiadiazoles 40a–m. Reagents and conditions: (i) NaOH, PTC, CHCl₃; (ii) H₂SO₄, EtOH, reflux, 3 h, thiosemicarbazide derivatives; (iii) EtOH, Et₃N, reflux, 3 h, Method A: diarylnitrilimines (DANI); Method B: N-aryl-C-ethoxycarbonylnitrilimines (NACE).

Figure 1

Chemical structures of the four thiadiazole isomers.

Figure 2

Chemical structures of FDA-approved drugs bearing 1,3,4-thiadiazole scaffold.

Scheme 1

Synthesis of the quinolone-based thiadiazoles 1a–j. Reagents and conditions: (i) Boc₂O, NaHCO₃, THF:H₂O (1:1), r.t., 24 h; (ii) ethyl chloroformate, TEA, dry DCM, r.t.; (iii) 4a–j, DCM, r.t., overnight; (iv) TFA, DCM 0 °C r.t., 4 h.

Scheme 2

Synthesis of thiadiazole honokiol derivatives 8a–j. Reagents and conditions: (i) I₂, EtOH/H₂O (1:9), 50 °C, 12 h; (ii) HCHO/NaOH, EtOH/H₂O (1:1), 50 °C; (iii) Zn, AcOH, EtOH, reflux at 78 °C, overnight, (iv) SOCl₂, DCM, 0 °C, 12 h; (v) 5-aryl-1,3,4-thiadiazole-2-amine, K₂CO₃, acetone, 50 °C, 12 h.

Figure 3

Two-dimensional binding mode of thiadiazole 8a in the active site of PI3Kα. Blue dotted lines: hydrogen bonds; light blue dotted lines: hydrophobic interactions; green dotted line: carbon hydrogen bond; purple dotted line: Pi–Pi T-shaped interaction, yellow dotted line: Pi–sulfur interaction.

Scheme 4

Synthesis of imidazothiadiazoles 18a–h. Reagents and conditions: (i) PhNCS, DMF, r.t.; (ii) EtOH, TEA, reflux 6 h.

Scheme 5

Synthesis of tris-thiadiazoles 22a–e. Reagents and conditions: (i) Ethanol, reflux, 4 h; (ii) isothiocyanate derivative, ethanol, reflux, 6 h, (iii) sulfuric acid, 0 °C, 30 min, r.t., 16 h.

Figure 4

Two-dimensional binding mode of thiadiazole 22d in the active site of LSD1. Blue dotted line: hydrogen bond; green dotted line: arene interactions.

Scheme 6

Synthesis of N-(1,3,4-thiadiazol-2-yl)benzamide derivatives 29a–t. Reagents and conditions: (i) trimethyl orthoformate, isopropanol, 85 °C, 0.5–1.5 h; di-methoxyaniline, 85 °C, 3–5 h; (ii) phenyl ether, 190 °C, 3–5 h; (iii) K₂CO₃, methyl 4-(chloromethyl)benzoate, DMF, 60 °C, 6–8 h; (iv) NaOH, H₂O, 45 °C, 2–3 h; (v) SOCl₂, CH₃Cl, DMF, 55 °C, 5–8 h; (vi) TEA, DCM, 0–5 °C, 8–10 h.

Scheme 7

Synthesis of the 1,3,4-thiadiazoles 32a–d. Reagents and conditions: (i) appropriate alkyl halide, K₂CO₃/acetone, r.t.; (ii) chloroacetyl chloride, K₂CO₃/DMF, r.t.; (iii) 1,3,4-thiadiazole-2,-dithiol, K₂CO₃/acetone, r.t.

Figure 5

Two-dimensional binding mode of thiadiazole 32a in the ATP-binding site of EGFR. Blue dotted lines: hydrogen bonds; green dotted line: arene interactions. In yellow the aminoacidic residues involved in hydrophobic interactions.

Scheme 8

Synthesis of thiadiazoles 36a–e. Reagents and conditions: (i) acetic acid, reflux, 3 h; (ii) ethyl cyanoacetate, TEA, absolute ethanol, stirring, 3 h; (iii) method A: appropriate aldehyde (for 36a–c) or 2-(4-methoxy-benzylidene) malonotrile (for 36d), absolute ethanol, piperidine, reflux, 3 h; method B: KOH, DMF, stirring, 30′, carbon disulfide, methyl iodide, r.t., 3 h, o-aminophenol, dioxane, TEA, reflux, 4 h (for 36e).

Figure 6

Schematic representation of key anticancer mechanisms of uncondensed thiadiazoles.

Figure 7

Schematic representation of the 2,5-disubstituted thiadiazoles with the highest anticancer potency, expressed as IC₅₀ values, and the most sensitive cancer cell lines.

Scheme 10

Synthesis of imidazo [2,1-b][1,3,4]thiadiazoles 43a–d. Reagents and conditions: (i) thiosemicarbazide, H₂SO₄, 60–70 °C, 8 h; (ii) EtOH, bromoacetyl derivative, 12 h, K₂CO₃; (iii) AcOH, Br₂, AcONa, 1 h; (iv) AcOH, Br₂, KSCN, 4 h; (v) DMF, POCl₃, 80 °C, 4 h.

Figure 8

Chemical structures of 3-(imidazo [2,1-b][1,3,4]thiadiazol-2-yl)-1H indole analogues 48a–q with potent antiproliferative activity.

Scheme 11

General synthesis of imidazothiadiazoles 47 and 48. Reagents and conditions: (i) H₂SO₄ conc, 60–70 °C, 8 h; (ii) TFA, 60 °C, 3.5 h; (iii) β-bromoacetyl compounds, anhydrous ethanol, reflux 24–48 h, (iv) POCl₃, DMF, 0–5 °C, DMF, 70 °C, 5 h.

Figure 9

Anticancer properties of the most potent imidazothiadiazoles of type 48.