Derivatives of 1,3,4-thiadiazoles for Various Applications in Drug Discovery, Agrochemistry, and Materials Technology

1,3,4-Thiadiazole is a sulfur-containing organic compound characterized by a molecular structure comprising a thiadiazole ring and two nitrogen atoms, forming a five-membered heterocyclic compound with a thiophene ring. Among its isomers, 1,3,4-thiadiazole has garnered more extensive research attention. Due to the inductive effect of the sulfur atom, the 1,3,4-thiadiazole ring exhibits weak basicity and relatively high aromaticity. It remains relatively stable in acidic aqueous solutions but undergoes ring cleavage in alkaline aqueous solutions. Additionally, owing to the electron-withdrawing effect of the nitrogen atoms, the ring is demonstrated to be electron-deficient, rendering it inert to electrophilic substitution but susceptible to nucleophilic attack. Introducing substituents at the 2' or 5' positions of the ring activates it, making it highly reactive and prone to forming various derivatives. Consequently, the properties of derivatives of 1,3,4-thiadiazole find widespread applications in fields such as medicine, agriculture, and materials chemistry.

Figure 1. Examples of medical and technological applications of the 1,3,4-thiadiazoles.

Derivatives of 1,3,4-thiadiazoles exhibit a diverse range of biological activities[1], finding extensive applications in the fields of medicine, agriculture, and materials technology[2,3]. Many compounds containing the 1,3,4-thiadiazole moiety demonstrate efficacy in medical applications, offering treatment solutions for various diseases. Currently, there are several commercially available drugs based on 1,3,4-thiadiazole (e.g., compounds 1 and 2 in Figure 1), and numerous drug candidates are undergoing various stages of clinical testing[4].

Sulfamethizole is a sulfonamide antibiotic employed in the treatment of a diverse range of susceptible bacterial infections. Sulfonamides, synthetic bacteriostatic antibiotics, possess a broad spectrum of activity against most gram-positive and many gram-negative organisms, although resistance may be observed in certain strains of a particular species. Acting as competitive inhibitors of p-aminobenzoic acid in the folic acid metabolism cycle, sulfonamides impede bacterial multiplication. Bacterial sensitivity remains consistent across various sulfonamides, and resistance to one implies resistance to all. While most sulfonamides are readily orally absorbed, their parenteral administration is challenging due to the highly alkaline and irritating nature of soluble sulfonamide salts.Sulfonamides are extensively distributed throughout all tissues, with elevated concentrations in pleural, peritoneal, synovial, and ocular fluids.

Although these antibiotics are no longer utilized for meningitis treatment, they exhibit high cerebrospinal fluid (CSF) levels in meningeal infections. Pus inhibits their antibacterial action. Sulfamethizole serves as a competitive inhibitor of the bacterial enzyme dihydropteroate synthetase, preventing the binding of the normal para-aminobenzoic acid (PABA) substrate. This inhibited reaction is essential in these organisms for the synthesis of folic acid.

Acetazolamide is a carbonic anhydrase inhibitor utilized in the treatment of edema associated with heart failure or medication, certain forms of epilepsy, and glaucoma. It differs from mercurial diuretics and is categorized as a nonbacteriostatic sulfonamide, exhibiting a chemical structure and pharmacological activity that are distinctly separate from bacteriostatic sulfonamides.

The anticonvulsant properties of Acetazolamide may be attributed to its direct inhibition of carbonic anhydrase in the central nervous system. This inhibition decreases carbon dioxide tension in the pulmonary alveoli, thereby raising arterial oxygen tension. The diuretic effects stem from the inhibition of carbonic anhydrase, leading to a diminished availability of hydrogen ions for active transport in the renal tubule lumen. Consequently, this results in alkaline urine and an augmented excretion of bicarbonate, sodium, potassium, and water.

Many derivatives of 1,3,4-thiadiazole have obtained patents in the agricultural field as herbicides, insecticides, fungicides[5], and crop protectants[6].

Due to the electron-deficient nature, excellent electron-accepting ability, as well as thermal and chemical stability of the 1,3,4-thiadiazole nucleus, thiadiazole finds extensive applications in optics and electrochemistry. Additionally, its applications are primarily focused on areas such as charge transfer capabilities, photo-induced luminescence, photoconductivity, intercalation properties for obtaining liquid crystals, and corrosion resistance in metals. The material applications of 1,3,4-thiadiazole encompass metal chelators[7], corrosion and oxidation inhibitors[8], optically active liquid crystals (e.g., compound 3 in Figure 1)[9], and photoelectron materials[10].

Reference

1. (a) Shadiha, S. K.; Thushara, B. S.; Marathakam, A.; Midhula, C. C.; Baijika, P. Intern. J. Pharm. Pharmaceut. Res. 2018, 12, 211-220. (b) Joseph, L.; George, M.; Mathews, P. J. Pharmaceut. Chem. Biol. Sci. 2015, 3, 329-345. (c) Matysiak, J. Mini-Rev. Med. Chem. 2015, 15, 762-775.

2. Hu, Y.; Li, C.-Y.; Wang, X.-M.; Yang, Y.-H.; Zhu, H.-L. Chem. Rev. 2014, 114, 5572-5610.

3. Koutentis, P.A.; Constantinides, C.P. in Comprehensive Heterocyclic Chemistry, 3rd edition, eds. A.R. Katritzky, C.A. Ramsden, E.F.V. Scriven, and R. J.K. Taylor, Pergamon, Oxford, 2008. Vol. 5, p. 568.

4. Information retrieved from the open database at www.drugbank.ca; accessed on April 2019.

5. Heil, M.; Erdelen, C.; Wachendorff-Neumann, U.; Turberg, A.; Mencke, N.; Gerd, H.; Klaus, S. PCT Int. Appl. WO 9 726 651 (1997) (Chem. Abstr. 1997, 127, 149148).

6. Diehr, H.-J. EU. Pat. 0 440 959 (1999) (Chem. Abstr. 1991, 115, 183323).

7. Bentiss, F.; Lagrenée, M.; Wignacourt, J.P.; Holt, E.M. Polyhedron 2002, 21, 403.

8. Gao, Y.; Zhang, Z.; Xue, Q. Mat. Res. Bull. 1999, 34, 1867.

9. Seed, A. Chem. Soc. Rev. 2007, 36, 2046.

10. Higashihara, T.; Wu, H.-C. Mizobe, T.; Chien Lu, C.; Ueda, M.; Chen, W.-C. Macromolecules 2012, 45, 9046.