An Understanding of Mechanism-Based Approaches for 1,3,4-Oxadiazole Scaffolds as Cytotoxic Agents and Enzyme Inhibitors

Abstract

The world’s health system is plagued by cancer and a worldwide effort is underway to find new drugs to treat cancer. There has been a significant improvement in understanding the pathogenesis of cancer, but it remains one of the leading causes of death. The imperative 1,3,4-oxadiazole scaffold possesses a wide variety of biological activities, particularly for cancer treatment. In the development of novel 1,3,4-oxadiazole-based drugs, structural modifications are important to ensure high cytotoxicity towards malignant cells. These structural modification strategies have shown promising results when combined with outstanding oxadiazole scaffolds, which selectively interact with nucleic acids, enzymes, and globular proteins. A variety of mechanisms, such as the inhibition of growth factors, enzymes, and kinases, contribute to their antiproliferative effects. The activity of different 1,3,4-oxadiazole conjugates were tested on the different cell lines of different types of cancer. It is demonstrated that 1,3,4-oxadiazole hybridization with other anticancer pharmacophores have different mechanisms of action by targeting various enzymes (thymidylate synthase, HDAC, topoisomerase II, telomerase, thymidine phosphorylase) and many of the proteins that contribute to cancer cell proliferation. The focus of this review is to highlight the anticancer potential, molecular docking, and SAR studies of 1,3,4-oxadiazole derivatives by inhibiting specific cancer biological targets, such as inhibiting telomerase activity, HDAC, thymidylate synthase, and the thymidine phosphorylase enzyme. The purpose of this review is to summarize recent developments and discoveries in the field of anticancer drugs using 1,3,4-oxadiazoles.

New Acetamide-Sulfonamide-Containing Scaffolds: Antiurease Activity Screening, Structure-Activity Relationship, Kinetics Mechanism, Molecular Docking, and MD Simulation Studies

“…For the last few decades, the search for effective and safe urease inhibitors has been a challenge for many scientists in the pharmaceutical industry. Since urease is linked to bacterial infections and there are currently very few urease inhibitors available, the design and synthesis of novel urease inhibitors is our prime research interest [ 8 , 9 , 10 ].…”

Exploring the potential of propanamide-sulfonamide based drug conjugates as dual inhibitors of urease and cyclooxygenase-2: biological and their in silico studies

“…Most toxins present in nature are natural enzyme inhibitors. Synthetic enzyme inhibitors find their application in treating diseases while acting as a drug ( Kumar et al, 2023 ; Yakan et al, 2023 ; Yu et al, 2023 ). Urease is urea amidohydrolase that catalyzes the hydrolysis of urea into carbon dioxide and ammonia, and it is found in many bacteria, fungi, and plants, as well as in some animals, including humans ( Tirmazi et al, 2021 ; Mehmood et al, 2022 ).…”

2-Substituted-3-(5-Substituted-1,3,4-oxadiazol/thiadiazol-2-yl) Thiazolidin-4-one Derivatives: Synthesis, Anticancer, Antimicrobial, and Antioxidant Potential

“…(Figure 1). The 1,3,4-thiadiazole-containing drugs Cefazolin and Nefazodone (antibiotics, cell wall synthesis inhibitors), Megazol (antiprotozole, protein, and DNA synthesis inhibitor), Methazolamide and Acetazolamide (diuretics, carbonic anhydrase inhibitors) Sulphamethizole (antimicrobial, dihydropteroate synthase inhibitor), and Azetepa (anticancer, alkylat-ing agent),and 1,3,4-oxadiazole-containing commercial drugs such as Furamizole (potent antibacterial action), Nesapidil (anti-arrhythmic action), Raltegravir (antiviral drug), Tiodazosin (antihypertensive agent), and the most promising FDA-approved derivative, the anticancer agent Zibotentan, are commercially available [20][21][22][23][24][25] (Figure 2). From this perspective, 1,3,4-oxadiazole/thiadiazole conjugates in medicinal chemistry have been developed rapidly and represent a significant approach to address the various drawbacks associated with anticancer and antimicrobial drugs, such as drug toxicity, drug resistance, and other serious side effects [26][27][28].…”

“…The 1,3,4-thiadiazole-containing drugs Cefazolin and Nefazodone (antibiotics, cell wall synthesis inhibitors), Megazol (antiprotozole, protein, and DNA synthesis inhibitor), Methazolamide and Acetazolamide (diuretics, carbonic anhydrase inhibitors) Sulphamethizole (antimicrobial, dihydropteroate synthase inhibitor), and Azetepa (anticancer, alkylating agent),and 1,3,4-oxadiazole-containing commercial drugs such as Furamizole (potent antibacterial action), Nesapidil (anti-arrhythmic action), Raltegravir (antiviral drug), Tiodazosin (antihypertensive agent), and the most promising FDA-approved derivative, the anticancer agent Zibotentan, are commercially available [ 20 , 21 , 22 , 23 , 24 , 25 ] ( Figure 2 ).…”