A computer-assisted approach was used to model and study privileged heterocyclic scaffolds containing dihydropyrazole, pyrimidin-2-amine, and thiazolidin-4-one moieties (hybrid pharmacophores) to obtain novel and promising antimicrobial prototype molecules. Main bioavailability descriptors were determined in order to assess the drug-likeness of the designed compounds and to pre-filter eleven compounds exhibiting the best profiles, thus passing to molecular docking study against a key penicillin-binding protein type-3 from enterotoxygenic E. coli. Seven structures were chosen by theirenergies of affinity and docking interactions with key residues in the active site of the receptor. Seven compounds with the highest docking scores belonging to the series of chalcones, dihydropyrazoles, aminopyrimidines, and thiazolidin-4-ones were prepared via condensation or cyclocondensation reactions. The structural elucidation of the final products was carried out by infrared spectra analysis and NMR experiments. Such molecular hybrids considered as potential hits in the search for new antibacterial compounds will be tested in vitro in further studies.

ExperimentalS2 General procedure for synthesis of 1-aryl-3-methyl-5-aminopyrazoles (3a-e). S2 1 H NMR spectrum of compound 3a S4 13 C NMR spectrum of compound 3a S5 1 H NMR spectrum of compound 3b S5 13 C NMR spectrum of compound 3b S6 1 H NMR spectrum of compound 3c S6 13 C NMR spectrum of compound 3c S7 1 H NMR spectrum of compound 3d S7 13 C NMR spectrum of compound 3d S8 1 H NMR spectrum of compound 3e S8 13 C NMR spectrum of compound 3e S9 General procedure for synthesis of synthesis of spiro[cyclohexane-1,4´-pyrazolo[3,4e][1,4]thiazepin]-7(6´H)-ones (4a-d). S9 1 H NMR spectrum of compound 4a S12 13 C NMR spectrum (Includes DEPT-135) of compound 4a S12 1 H NMR spectrum of compound 4b S13 13 C NMR spectrum (Includes DEPT-135) of compound 4b S13 1 H NMR spectrum of compound 4c S14 13 C NMR spectrum (Includes DEPT-135) of compound 4c S14 1 H NMR spectrum of compound 4d S15 13

In the search for new intermediates for heterocyclic synthesis, the reactivity of 6‐iminophosphoranepyrimidines against dimethyl acetylenedicarboxylate (DMAD) and ethyl propiolate as dienophiles, was studied in this work. The presence of a viable 2‐azadienic moiety in pyrimidin‐4‐one rings (oxo derivatives) favored reaction of DMAD by [4 + 2]/retro‐[4 + 2] sequence, in addition to the expected [2 + 2] cycloaddition/retrocycloaddition involving phosphazene moiety. In contrast, pyrimidine derivatives lacking a viable 2‐azadienic residue reacted only through phosphazene group by the aforementioned [2 + 2]/retro‐[2 + 2] tandem process. Ethyl propiolate (non‐symmetric dienophile) proved less reactive in the study, giving rise to undesired side reactions.