<p>In this multitarget study, a new series of eighteen 1,3,5-triazine-based sulfonamides incorporating chlorine/hydrazine and variable amine structural motifs was synthesized, proved for the chemical structure and product purity, and tested via molecular modeling to predict their biological activity. Selection of a potentially relevant biological target(s) for these derivatives for their future in-vitro experiments was based on molecular modeling inhibition study through a wide scale of enzymes linked with inflammatory (COX-1 vs. COX-2), oncology (PSMA, hCA II vs. IX, XII, CDK1), microbial (FtsZ) and autoimmune (JAK-1, JAK-2) diseases. Molecular docking revealed a poor stability (usually below 70% of a reference standard) of the majority of the tested derivatives and their precursors for PSMA, FtsZ and JAK receptors. On the other hand, much better - generally similar or only a bit less stable associates compared to a reference drug (dinaciclib) were observed with tumor-associated receptor CDK1. Many of the derivatives and their precursors created enzyme-substrate associates with excellent - comparable or even higher stability than reference acetazolamide-hCA IX and hCA XII associates; selectivity of the association with physiological hCA II and tumor-associated hCAs was excellent for hCA XII, while for hCA IX it was not so pronounced. Molecular docking indicated the derivatives and their precursors created relatively highly stable associates with COX-2, having the docking/glide score for many of them to be close to the reference drug celecoxib and the selectivity COX-2/COX-1 even exceeding that of celecoxib. Hence, a new series of triazine-based sulfonamides is proposed for further consideration as potential COX-2 selective anti-inflammatory agents, and hCA (IX, XII) and CDK-1-based (selective) antitumor agents. The study also indicated (and confirmed by molecular dynamics calculations) exceptional derivatives exhibiting reasonable stability across all or almost all tested enzyme receptors.</p>