An efficient synthesis of mono-, di-, and tri-substituted 1,3-thiazoles employing functionalized thioamides as thiocarbonyl precursors.

Herein, we report an efficient strategy to synthesize functionalized 1,3-thiazoles using alkyl 2-amino-2-thioxoacetates. Thioamides, the synthetic precursors, react effortlessly with electrophilic reagents and are transformed into a series of phenyl-, methyl-, and acyl-substituted thiazoles with high functionalization at the 2nd position through sequential C-S/C-N bond formation. Rapid reaction times under metal-free mild conditions is a noteworthy feature of the reported protocol. Given the intriguing biological significance of the synthesized molecules, we further performed a comprehensive evaluation of their potency against the SARS-CoV-2 receptor (PDB ID: 7mc6) using a molecular docking approach, with binding scores ranging from -4.3 to -8.2 kcal mol-1.

Regioselective Synthesis of 2,5-Disubstituted-1,3,4-thiadiazoles and 1,3,4-Oxadiazoles via Alkyl 2-(Methylthio)-2-thioxoacetates and Alkyl 2-Amino-2-thioxoacetates.

An acid-catalyzed regioselective cyclization reaction of 2,5-disubstituted-1,3,4-thiadiazoles and 1,3,4-oxadiazoles has been developed. The synthetic precursors alkyl 2-(methylthio)-2-thioxoacetates/alkyl 2-amino-2-thioxoacetates react efficiently with acyl hydrazides, which transformed into a series of dehydrative and desulfurative products with employment of p-TSA and AcOH through a regioselective cyclization process. The alkyl 2-amino-2-thioxoacetate pathway generates excellent yield among the mentioned procedures. The reported methods are operationally simplistic and highly efficient with metal-free conditions and demonstrate significant functional group compatibility. Regioselective cyclized products were confirmed by single-crystal X-ray diffraction studies.

The regioselective synthesis of 2,5- and 4,5-disubstituted thiazoles via the cyclization of 2-oxo-2-(amino)ethanedithioates with isocyanides.

The regioselective synthesis of 2-(methylthio)-N-aryl/alkylthiazole-5-carboxamides and ethyl-5-(aryl/alkyl carbamoyl)thiazole-4-carboxylates was carried out via the base-induced cyclization of methyl-2-oxo-2-(amino)ethanedithioates with TosMIC and ethyl isocyanoacetate, respectively, with high yields. The regioisomeric products were confirmed based on X-ray diffraction studies. An advantage of the present method is the wide-ranging isocyanide reactivity compared to earlier protocols, while the catalyst-free nature and rapid reaction times are noteworthy features.

Base Induced Condensation of Malononitrile with Erlenmeyer Azlactones: An Unexpected Synthesis of Multi-Substituted Δ2 -Pyrrolines and Their Cytotoxicity.

An efficient, metal free approach to synthesize multi-substituted Δ2 -pyrroline derivatives by mild base catalyzed cyclocondensation of malononitrile with Erlenmeyer azlactones via 1,2 addition was developed. The modularity of this reaction was used to assemble a range of poly-substituted pyrrolines. Further, synthesized products were screened for cytotoxic properties on different cancer cell lines such as A549 (Human lung adenocarcinoma cells), HeLa (Human cervical adenocarcinoma cells), Jurkat (Human chronic myeloid leukemia cells) and K562 (Human leukemic T cell Lymphoblast cells). Among the synthesized library of compounds, 6f and 6q displayed potent cytotoxic activity.

The reaction of arylmethyl isocyanides and arylmethylamines with xanthate esters: a facile and unexpected synthesis of carbamothioates.

An unexpected formation of carbamothioates by a sodium hydride-mediated reaction of arylmethyl isocyanides with xanthate esters in DMF is reported. The products thus obtained were compared with the carbamothioates obtained by the sodium hydride-mediated condensation of the corresponding benzylamines and xanthate esters in DMF. To account for these unexpected reactions, a mechanism is proposed in which the key steps are supported by quantum chemical calculations.

Synthesis of new coumarin tethered isoxazolines as potential anticancer agents.

A series of new coumarin tethered isoxazolines (7a-l) were synthesized and evaluated for their cytotoxic potency against human melanoma cancer cell line (UACC 903) as well as fibroblast normal cell line (FF2441). Preliminary results revealed that some of these coumarin tethered isoxazolines 7b, 7c, 7f and 7j exhibited significant antiproliferative effect against human melanoma cancer (UACC 903) with IC50 values of 8.8, 10.5, 9.2 and 4.5 µM respectively. However, compound 7c was non-toxic to normal human cells at the tested concentration. Further, we have chosen compound 7c to check its efficacy in Ehrlich Ascites Carcinoma animal model in-vivo for its antitumor and antiangiogenic properties. Our lead compound significantly reduced the cell viability, body weight, ascites volume and downregulated the formation of neovasculature such as regression of tumor volume. The present study indicates the scope of developing into potent anticancer drug in near future.

A non-cytotoxic N-dehydroabietylamine derivative with potent antimalarial activity.

Malaria caused by the Plasmodium parasites continues to be an enormous global health problem owing to wide spread drug resistance of parasites to many of the available antimalarial drugs. Therefore, development of new classes of antimalarial agents is essential to effectively treat malaria. In this study, the efficacy of naturally occurring diterpenoids, dehydroabietylamine and abietic acid, and their synthetic derivatives was assessed for antimalarial activity. Dehydroabietylamine and its N-trifluoroacetyl, N-tribromoacetyl, N-benzoyl, and N-benzyl derivatives showed excellent activity against P. falciparum parasites with IC50 values of 0.36 to 2.6 µM. Interestingly, N-dehydroabietylbenzamide showed potent antimalarial activity (IC50 0.36), and negligible cytotoxicity (IC50 >100 µM) to mammalian cells; thus, this compound can be an important antimalarial drug. In contrast, abietic acid was only marginally effective, exhibiting an IC50 value of ~82 µM. Several carboxylic group-derivatives of abietic acid were moderately active with IC50 values of ~8.2 to ~13.3 µM. These results suggest that a detailed understanding of the structure-activity relationship of abietane diterpenoids might provide strategies to exploit this class of compounds for malaria treatment.

Facile synthesis of antimalarial 1,2-disubstituted 4-quinolones from 1,3-bisaryl-monothio-1,3-diketones.

A new strategy was developed to synthesize 1,2-disubstituted 4-quinolones in good yield starting from 1,3-bisaryl-monothio-1,3-diketone substrates. The synthesized compounds were evaluated for antimalarial activity using Plasmodium falciparum strains. All compounds, except for two, showed good activity. Of these, seven compounds exhibited an excellent antimalarial activity (IC50, <2 µM). More importantly, all seven compounds were equally effective in inhibiting the growth of both chloroquine-sensitive and chloroquine-resistant strains. The cytotoxicity assessment using carcinoma and non-carcinoma human cell lines revealed that almost all synthesized compounds were minimally cytotoxic (IC50, >50 µM).