Design, Regiospecific Green Synthesis, Chemical Computational Analysis, and Antimicrobial Evaluation of Novel Phthalazine Heterocycles

Abstract

Phthalazines have received considerable attention for their wide antimicrobial activity. Regiospecific nucleophilic attack of 4‐benzylphthalazin‐1‐ol by the 1‐oxo rather than the aza group on different alkyl halides gave novel phthalazine heterocyclic derivatives. Moreover, a variety of nucleosides bonded to electron‐withdrawing groups were synthesized using 4‐benzylphthalazine‐1‐ol. The density functional theory has been used to investigate the electronic structure of the synthesized compounds. All of the synthesized derivatives showed remarkable activity when tested against Gram‐positive and Gram‐negative bacteria, Aspergillus niger, and Candida albicans. The reactivity of these nucleosides was expected to arise from their bonding with the lone pair of N‐atom of the macromolecules of bacteria. These bonding were expected to inhibit the enzyme by forming highly stable complex with lower highest occupied molecular orbital energy. The structures of these synthesized derivatives were established by Fourier transform infrared, 1H‐NMR, and 13C‐NMR spectroscopic evidence.

Preparation and Uses of Chlorinated Glycerol Derivatives

“…Chlorohydrins and ECH were used to prepare derivatives of pyridine [139][140][141], phtalazines [142][143][144], oxazolidinone [122,145,146], triazinones [147], thioglycoside [148] and aziridines [149]. N-Heterocycles have wide applicability as antibiotics [150][151][152].…”

“…The reaction of 1,3-DCH and ECH with arylphthalazinone yielded phthalazin derivatives [142][143][144]147]. Figure 18a shows the N-alkyl products resulting from the nucleophilic attack of the nitrogen in the phthalazinone on 1,3-DCH (33% to 36% yield) or ECH (51% to 54% yield).…”

“…This attack was promoted by the presence of K 2 CO 3 . The loss of aromaticity, when an aryl radical was substituted by a benzyl radical, allowed the regiospecific nucleophilic attack of the oxygen instead of the nitrogen on 1,3-DCH and ECH (Figure 18b) [144]. The reaction of ECH occurred via ring opening-ring closing of the oxirane nucleus (54% yield), while the reaction with 1,3-DCH, was described as a SN 2 reaction to yield O-(3-chloro-2-hydroxypropyl) phthalazine (36% yield).…”

“…(a) Synthesis of N-alkylated phtalazines[142]; (b) synthesis of 1-oxo alkylated phtalazine[144]; (c) synthesis of Se-and S-alkyl phthalazines derivatives[143].…”

Synthesis, DFT and antimicrobial studies of 5,6,7,8-Tetrachloro Phthalazin-1(2H)-one derivatives

“…Also in terms of this aspect, many studies have been focused on pyridazin-(3H)-ones, which are characterized to possess good analgesic and antiinflammatory activities. Besidespyridazinones, these studies have indicated that the heterocyclic ring substitutions at the six position, and the presence of acetamide side chain when linked to the lactam nitrogen of pyridazinone ring at the two position of the pyridazinone ring, improve the analgesic and antiflammatory activity along with nil or very low ulcerogenicity [27][28][29][30] . In view of the aforementioned facts, it seemed most interesting to synthesize some [4-((3-chloro-4methylphenyl)-2-substituted phthalazin-1(2H)one] derivatives with the aim to obtain more precise information about the course of reactions and biological activities.…”