Novel thiazolidine-2,4-dione carboxamide and amino acid derivatives were synthesized in excellent yield using OxymaPure/N,N′-diisopropylcarbodimide coupling methodology and were characterized by chromatographic and spectrometric methods, and elemental analysis. The antimicrobial and antifungal activity of these derivatives was evaluated against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), two-Gram negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and one fungal isolate (Candida albicans). Interestingly, several samples demonstrated weak to moderate antibacterial activity against Gram-negative bacteria, as well as antifungal activity. However, only one compound namely, 2-(5-(3-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl)acetic acid, showed antibacterial activity against Gram-positive bacteria, particularly S. aureus.

A novel series of 4,6-disubstituted s-triazin-2-yl amino acid derivatives was prepared and characterized. Most of them showed antifungal activity against Candida albicans compared to clotrimazole (standard drug). Compounds bearing aniline derivatives, piperidine and glycine on the triazine core showed the highest inhibition zones at concentrations of 50, 100, 200, and 300 μg per disc. In addition, docking studies revealed that all the compounds accommodated well in the active site residues of N-myristoltransferase (NMT) and exhibited complementarity, which explains the observed antifungal activity. Interestingly, none of these compounds showed antibacterial activity.

Several derivatives containing morpholine/piperidine, anilines, and dipeptides as pending moieties were prepared using s-triazine as a scaffold. These compounds were evaluated for their anticancer activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231), a colon cancer cell line (HCT-116), and a non-tumorigenic cell line (HEK 293). Tamoxifen was used as a reference. Animal toxicity tests were carried out in zebrafish embryos. Most of these compounds showed a higher activity against breast cancer than colon cancer. Compound 3a—which contains morpholine, aniline, and glycylglycinate methyl ester—showed a high level of cytotoxicity against MCF-7 cells with IC₅₀ values of less than 1 µM. This compound showed a much lower level of toxicity against the non-tumorigenic HEK-293 cell line, and in the in vivo studies using zebrafish embryos. Furthermore, it induced cell cycle arrest at the G2/M phase, and apoptosis in MCF-7 cells. On the basis of our results, 3a emerges as a potential candidate for further development as a therapeutic drug to treat hormone receptor-positive breast cancer.

A simple, cost-effective method under environmentally benign conditions is a very important concept for the preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives. The present work describes an efficient and eco-friendly protocol for the synthesis of 2-amino-N-(2-substituted-ethyl)benzamide and 3-substituted-2,3-dihydroquinazolin-4(1H)-one derivatives. The novel feature of this protocol is the use of 2-methyl tetrahydrofuran (2-MeTHF) as an eco-friendly alternative solvent to tetrahydrofuran (THF) in the first step. In the second step, methanol in the presence of potassium carbonate as a catalyst was used under conventional heating or microwave irradiation, which provided an eco-friendly method to afford the target products in excellent yields and purities. NMR (¹H and ¹³C), elemental analysis, and LC-MS confirmed the structures of all compounds. X-ray crystallography further confirmed the structure of the intermediate 2-amino-N-(2-substituted-ethyl)benzamide 3a. The molecular structure of 3a was monoclinic crystal, with P21/c, a = 13.6879 (11) Å, b = 10.2118 (9) Å, c = 9.7884 (9) Å, β = 105.068 (7)°, V = 1321.2 (2) Å3, and Z = 4.

2,4,6-Trichloro-1,3,5-triazine (TCT) offers the unique ability to undergo sequential nucleophilic substitution reactions using regular nucleophiles (first Cl replacement at 0 °C, second at RT, and third at >90 °C), making s-triazine a privileged scaffold-finding application in drug development with an extension towards the development of new materials. This selective chemical property of TCT fulfills the goal of chemists to control organic structures and make them react in the required conditions for achieving each objective. In this regard, orthogonality and chemoselectivity are two modern organic chemistry concepts which have been exploited in various areas of research, ranging from supramolecular chemistry to organic/bioconjugation chemistry. We have demonstrated the fusion of these two concepts using TCT as “Orthogonal Chemoselectivity” and defined it as discrimination between reactive sites in any order. The usage of azide as one of the nucleophiles modulated the reactivity of the s-triazine core for the last Cl replacement. This allowed us to overcome the barrier of higher temperature (>90 °C) for the last Cl replacement which happened at RT, taking advantage of side chains of Cys, Tyr and Lys in a biological context. In this presentation, we revise the chemistry developed in our laboratories to manipulate the TCT core for application in our medicinal chemistry programs and in bioconjugation.