In the quest for better medicines, a simple atomic swap is opening new frontiers in drug discovery.
For decades, the synthesis of sulfur-containing molecules called thioamides relied on methods that were inefficient, toxic, or environmentally damaging. Today, chemists are pioneering cleaner, more practical approaches using elemental sulfur and other sustainable sulfur sources. These advances are not just academic curiosities—they're paving the way for more effective treatments for diseases ranging from tuberculosis to COVID-19, all while making chemical manufacturing greener.
At first glance, a thioamide looks nearly identical to the common amide group found in proteins and many pharmaceuticals. The only difference? A single atom swap—sulfur replaces oxygen. Yet this subtle change creates a world of difference in chemical behavior and biological activity6 .
Thioamides are fascinating isosteres of canonical amide bonds6 . The sulfur atom makes them stronger hydrogen bond donors but weaker hydrogen bond acceptors compared to their oxygen-containing cousins. They also have a special affinity for certain metals and can be developed as metal complexes and chelators6 .
Amide
Oxygen atomThioamide
Sulfur atomThis single atom substitution significantly alters chemical properties and biological activity.
This unique chemistry translates into important medical applications. Several FDA-approved drugs already contain thioamide structures6 :
Ethionamide and prothionamide for multidrug-resistant tuberculosis.
Tioguanine and mercaptopurine for leukemia.
Fimasartan for hypertension and heart failure.
Thioamides in novel SARS-CoV-2 3CLpro inhibitors8 .
Traditional methods for creating thioamides often involved Lawesson's reagent or P4S10—compounds that can be expensive, difficult to handle, and generate substantial waste2 . Over the past decade, chemists have shifted toward more sustainable approaches, with elemental sulfur emerging as a star player2 .
Elemental sulfur checks all the boxes for green chemistry: it's nontoxic to humans, naturally abundant, easily available with high purity, stable under ambient conditions, and inexpensive2 . The challenge has been activating it to perform the specific chemical transformations needed to create thioamides.
The classic Willgerodt-Kindler reaction, which combines carbonyl compounds, amines, and sulfur to make thioamides, has been known for over a century. But the traditional process often required high temperatures, organic solvents, and produced complex mixtures2 .
A groundbreaking study published in 2025 demonstrates just how far thioamide synthesis has come1 . The research team developed an remarkably efficient method for creating alkyl thioamides through a one-pot, three-component reaction.
Combine allyl alcohols, elemental sulfur (S₈), and amines in a single reaction vessel1 .
Heat the mixture to initiate the reaction1 .
No complex purification steps required1 .
The method achieved outstanding results across a broad range of starting materials1 :
Approaching the theoretical maximum yield for thioamide synthesis.
Works with both aromatic cinnamyl alcohols and linear allyl alcohols.
Successful application with cyclic amines and long-chain primary amines.
Efficient scale-up demonstrating potential for industrial applications.
Perhaps most impressively, this approach represents a perfect marriage of practicality and environmental responsibility. By eliminating solvents and hazardous reagents, it reduces waste and simplifies purification while maintaining high efficiency.
| Allyl Alcohol Starting Material | Amine Used | Thioamide Product Yield |
|---|---|---|
| Cinnamyl alcohol | Morpholine | 94% |
| Cinnamyl alcohol | Piperidine | 97% |
| Cinnamyl alcohol | Butylamine | 89% |
| Linear allyl alcohol | Piperidine | 85% |
| Linear allyl alcohol | Morpholine | 82% |
| Reagent | Function in Thioamide Synthesis |
|---|---|
| Elemental Sulfur (S₈) | Serves as oxidant and sulfur source; nontoxic, abundant, and easy to handle2 . |
| Allyl Alcohols | Act as versatile starting materials that can be converted to corresponding aldehydes in situ1 . |
| Amines | Nitrogen source for the thioamide backbone; both cyclic and linear amines are effective1 . |
| DMF | In some reactions, acts as both solvent and reactant, providing dimethylamine groups2 . |
| Copper Catalysts | Essential for maintaining chirality in peptide synthesis; prevents racemization2 . |
| Water | Emerging as green solvent for certain thioamide reactions; enables reactions without organic solvents2 . |
The implications of these synthetic advances extend far beyond academic interest. Improved thioamide synthesis enables the development of better pharmaceuticals, as thioamides can enhance drug stability and efficacy6 .
In antiviral research, thioamide-containing compounds have shown significant promise against SARS-CoV-2. Recent work on thioamide-linked spiropyrrolidine derivatives produced a compound with impressive antiviral activity (EC₅₀ = 0.52 μM) and low cytotoxicity8 . The researchers specifically designed these molecules with thioamides to provide better resistance to enzymatic degradation compared to oxygen-containing analogs8 .
In cancer research, thioamide-containing compounds are being developed as inhibitors of key enzymes like ALK5 and ASH1L, which play important roles in tumor growth and metastasis6 .
| Therapeutic Area | Example Compounds | Biological Target or Activity |
|---|---|---|
| Infectious Diseases | Ethionamide, Prothionamide | Second-line tuberculosis treatment6 |
| COVID-19 | Thioamide-linked spiropyrrolidines | SARS-CoV-2 3CLpro inhibition8 |
| Cancer | A-83-01, AS-5 | ALK5 and ASH1L inhibition6 |
| Autoimmune Conditions | Tioguanine, Mercaptopurine | Antimetabolites for leukemia and inflammatory bowel disease6 |
| Cardiovascular Disease | Fimasartan | Angiotensin II receptor blocker for hypertension6 |
As thioamide synthesis continues to evolve, researchers are exploring even more sustainable and efficient approaches. Recent developments include late-stage functionalization strategies that allow chemists to introduce thioamides into complex molecules without having to rebuild them from scratch.
The ongoing optimization of one-pot methods that minimize purification steps and reduce waste represents another exciting frontier. These approaches align with the broader goals of green chemistry, making pharmaceutical manufacturing more environmentally friendly without compromising efficiency.
The remarkable progress in thioamide synthesis over the past decade demonstrates how creative thinking can transform traditional chemical processes into models of sustainability. As researchers continue to refine these methods, we can expect even more innovative approaches to emerge—further bridging the gap between chemical synthesis and environmental responsibility.
From tackling drug-resistant tuberculosis to developing new antiviral therapies, these sulfur-containing molecules are proving their worth in modern medicine, enabled by synthetic methods that are as practical as they are ingenious.