1,3,4-Thiadiazole and its Derivatives: A Review on Recent Progress in Biological Activities Abhishek Kumar Jain 1, *, Simant Sharma 1 , Ankur Vaidya 1 , Veerasamy Ravichandran 2 and Ram Kishore Agrawal 1, * 1 Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Sciences,Dr. Hari Singh Gour University,Sagar,Madhya Pradhesh,470 003,India 2 Faculty of Pharmacy,AIMST University,Semeling,08100, Kedah,Malaysia *Corresponding authors: Abhishek Kumar Jain, abhishekjain2105@rediffmail.com; and Ram Kishore Agrawal, ramkishoreagrawal@gmail.com The 1,3,4-thiadiazole nucleus is one of the most impor- tant and well-known heterocyclic nuclei, which is a common and integral feature of a variety of natural products and medicinal agents. Thiadiazole nucleus is present as a core structural component in an array of drug categories such as antimicrobial, anti-inflamma- tory, analgesic, antiepileptic, antiviral, antineoplastic, and antitubercular agents. The broad and potent activ- ity of thiadiazole and their derivatives has established them as pharmacologically significant scaffolds. In this study, an attempt has been made with recent research findings on this nucleus, to review the structural modi- fications on different thiadiazole derivatives for various pharmacological activities. Key words: 1,3,4-thiadiazole, antimicrobial, thiadiazole 1,3,4-thiadazoles have become an important class of het- erocycles and a great interest of researches because of their broad types of biological activity. Thiadiazole is a 5- membered ring system containing hydrogen-binding domain, sulfur atom, and two-electron donor nitrogen sys- tem that exhibit a wide variety of biological activity. They occur in four isomeric forms in the nature viz. 1,2,3-thi- adiazole; 1,2,5-thiadiazole; 1,2,4-thiadiazole; and 1,3,4-thi- adiazole (Scheme 1). Many drugs containing 1,3,4-thiadiazole nucleus such as acetazolamide 1, methazolamide 2, megazol 3 are avail- able in the market, although the only commercial 1,2,4-thi- adiazole drug is the antibiotic cefozopram [1,2]. S N N N H C H 3 S NH 2 O O O S N N N C H 3 S NH 2 O O C H 3 O S N N N N CH 3 NH 2 O 2 N 1 2 3 The present review, emphasizes on the biological activities revealed by substituted 1,3,4-thiadiazoles and structurally related thiadiazoles. The review covers advances made in the last 10 years and provides discussion on SAR. Biological activity of 4-thiazolidinones There are several reports in the literature describing the 1,3,4-thiadiazole derivatives for their various biological activities and the most relevant and recent studies have revealed that 1,3,4-thiadiazole derivatives have a broad spectrum of pharmacological activities that can be classi- fied into the following categories. Antibacterial and Antifungal activity 1,3,4-Thiadiazole has shown a broad spectrum of activity against various pathogens, and extensive research has been performed on the synthesis of new potent antibacte- rial and antifungal agents. A new series of 2-[[1(2H)-phtha- lazinone-2-yl]methyl/ethyl]-5-arylamino-1,3,4-thiadiazole derivatives (4) was evaluated in vitro antimicrobial activity against bacteria and fungal species. The results showed that the tested compounds possessed weak antibacterial and antifungal activity compared with standard drugs chl- oramphenicol and rifampicin for antibacterial and ketoco- nazole for antifungal activity, respectively [3]. A number of 5-substituted 2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole derivatives (5) have been evaluated for antifungal activity against several clinical isolates of Candida albicans. The compounds with methyl, phenyl, 4-ethoxyphenyl, and halogenophenyl groups at C-2 of thiadiazole ring showed higher antifungal activity [4]. N S N N N O C H 2 N H R n N S N N H R O H OH 5 4 R = -CH3, -C6H5, -CH2C6H5, 4-Cl-C6H4, 4-OCH3- C6H4, 4-CH3- C6H4, 2,4- di-ClC6H3; n = 1,2 N S N N S N NN S N S N Scheme 1: Thiadiazole structures. ª 2013 John Wiley & Sons A/S. doi: 10.1111/cbdd.12125 557 Chem Biol Drug Des 2013; 81: 557–576 Review