Chemistry and Biological Activities of 1,2,4-Triazolethiones—Antiviral and Anti-Infective Drugs

Mercapto-substituted 1,2,4-triazoles are very interesting compounds as they play an important role in chemopreventive and chemotherapeutic effects on cancer. In recent decades, literature has been enriched with sulfur- and nitrogen-containing heterocycles which are used as a basic nucleus of different heterocyclic compounds with various biological applications in medicine and also occupy a huge part of natural products. Therefore, we shed, herein, more light on the synthesis of this interesting class and its application as a biologically active moiety. They might also be suitable as antiviral and anti-infective drugs.


Introduction
Taribavirin (I) ( Figure 1) is a triazole based clinically used as antiviral drugs ( Figure 1). It is an active agent against a number of DNA and RNA viruses. It is indicated for severe respiratory syncytial virus (RSV) infection, hepatitis C infection, and other viral infections like the West Nile virus and dengue fever [1][2][3]. Taribavirin (also known as viramidine) is an antiviral drug in Phase III human trials, but not yet approved for pharmaceutical use [4]. AIDS is characterized by an abnormal host defense mechanism that predisposes to infections with opportunistic microorganisms [5]. It was reported [6] that compounds IIIa-d ( Figure 1) have been proved as treatment for HIV-1. The viral enzymes, reverse transcriptase (RT), integrase (IN), AIDS is characterized by an abnormal host defense mechanism that predisposes to infections with opportunistic microorganisms [5]. It was reported [6] that compounds IIIa-d ( Figure 1) have Molecules 2020, 25 been proved as treatment for HIV-1. The viral enzymes, reverse transcriptase (RT), integrase (IN), and protease (PR) are all good drug targets. Two distinct types of RT inhibitors, both of which block the polymerase activity of RT, have been approved to treat HIV-1 infections, nucleoside analogs (NRTIs), and nonnucleosides (NNRTIs), and there are promising leads for compounds that either block the RNase H activity or block the polymerase in other ways. A better understanding of the structure and function(s) of RT and of the mechanism(s) of inhibition can be used to generate better drugs; in particular, drugs that are effective against the current drug-resistant strains of HIV-1.NNRTIs via high throughput screening (HTS) using a cell-based assay for inhibiting HIV-1 replication and promising activities against selected NNRTI-resistant mutants such as Y181L, Y181C, K103N, and L100I were observed. Sulfanyltriazoles IIIa and IIIc ( Figure 1) exhibited EC50 values of 182 and 24 nM, respectively, suggesting the potential of these sulfanyltriazoles to overcome the K103-related NNRTI-resistant mutants. These sulfanyltriazoles could serve as advanced lead structures promising great potential in overcoming these and other NNRTI-resistant mutants [7].
Sulfanyltriazoles IIIa and IIIc ( Figure 1) exhibited EC50 values of 182 and 24 nM, respectively, suggesting the potential of these sulfanyltriazoles to overcome the K103-related NNRTI-resistant mutants. These sulfanyltriazoles could serve as advanced lead structures promising great potential in overcoming these and other NNRTI-resistant mutants [7].
obtained by reaction of 60a-e with hydrazine hydrate, were condensed with various isothiocyanates to yield the corresponding hydrazinecarbothioamides 62a-e. Further, 1,2,4-Triazole-3-thiones 63a-e were synthesized in 44-75% yields from the cyclization 62a-e in basic media (Scheme 14) [47]. Screening of compounds 63a-e for in vitro antifungal and antibacterial activity revealed that they have the best antifungal activity compared with the reference bifonazole in addition to the same bactericidal activity as streptomycin, except for Enterobacter cloacae and Salmonella species [47]. Various thiosemicarbazide derivatives 65a-c were then synthesized from the reaction of acid hydrazides 64a-c with 3-fluorophenyl isothiocyanates. Further, 1,2,4-triazole-3-thiones 66a-c were obtained from alkaline cyclization of compounds 65a-c with 8% NaOH solution (Scheme 16) [40].
yield. The synthesis of triazolethione Schiff bases 162a-i was achieved, in 35-66% yield, by refluxing of 161 with different aromatic aldehydes. Besides, Mannich bases 163a-h were easily obtained from the reaction of Schiff bases 162a-i with formaldehyde and morpholine in 39-82% yields (Scheme 43) [73]. The antimicrobial bioassay of these compounds 163a-h showed that antimicrobial activity was increased by introducing azomethine group and also by the addition of morpholine group leading to prospective antimicrobial agents with 163a-b, 163e-f, and 163h [73].

Synthesis of Open-Chain Compounds
The synthesis of mono and bipolar surfactants 201a-d and 202a-d was achieved by the reaction Scheme 55 . Formation of triazolothiones 199a,b.
The reaction of aminotriazolethiones 243a-i with different aldehydes afforded various arylidenes 244a-l, which upon reacting with 133 gave substituted triazoles 245a-i (Scheme 67). The bioassay of antibacterial and antifungal activities of 245a-i revealed that they have better antifungal than antibacterial activities; also, compounds 245b,c,f,j,k,l showed excellent antifungal activity against Candida albicans with an MIC of 16 μg/mL [93].

Scheme 67. Synthesis of substituted triazoles 245a-i.
Mannich reaction of arylidene derivatives of triazolethiols 246 with formaldehyde and benzyl piperazine or 4-substituted pyrimidyl/phenyl/pyridylpiperazine in ethanol at room temperature led to new Mannich bases 247a-c and 248a-c in 67-74% and 72-83% yields, respectively [94] (Scheme 68). The bioassay of the synthesized compounds revealed that these compounds could be used as new fungicides, whereas compounds 247a-c exhibited higher and wider fungicidal activities comparable with that of control triadimefon (Scheme 68) [94].

Synthesis of Triazolothiadiazoles
Triazolo [3,4-b] [1,3,4]thiadiazoles 276a-g and 277a-e were obtained from refluxing of different aromatic carboxylic acids with 11o in the presence of phosphorous oxychloride [105]. Screening of the synthesized compounds against lung carcinoma (H157) and kidney fibroblast cell lines  showed that compound 277d has the highest inhibition activity of 74.0% for BHK-21 cells which is the same as that of standard drug vincristine (74.5%). Compound 276c,d,g showed less inhibition values , and triazolothidiazole 276a was the most potent compound with inhibition value of 85.5%, whereas compounds 276b,f and 277a exhibited less inhibition values (Scheme 82) [105].

Synthesis of Triazolothiadiazoles
Triazolo [3,4-b] [1,3,4]thiadiazoles 276a-g and 277a-e were obtained from refluxing of different aromatic carboxylic acids with 11o in the presence of phosphorous oxychloride [105]. Screening of the synthesized compounds against lung carcinoma (H157) and kidney fibroblast cell lines  showed that compound 277d has the highest inhibition activity of 74.0% for BHK-21 cells which is the same as that of standard drug vincristine (74.5%). Compound 276c,d,g showed less inhibition values, and triazolothidiazole 276a was the most potent compound with inhibition value of 85.5%, whereas compounds 276b,f and 277a exhibited less inhibition values (Scheme 82) [105].

Conclusions
In this review, we are trying to focus attention on the routes of triazole-thione synthesis. Since, triazolethione-thiols have gained considerable importance in medicinal chemistry, due to their broad spectrum as antiviral, antibacterial, anticancer, etc. agents, their synthesis has become of great interest. We also give spots on the biology of the target molecule as prospective antiviral drugs.