Facile Synthesis and Antimicrobial Evaluation of Some New Heterocyclic Compounds Incorporating a Biologically Active Sulfamoyl Moiety

A facile and convenient synthesis of new heterocyclic compounds containing a sulfamoyl moiety suitable for use as antimicrobial agents was reported. The precursor 3-oxo-3-phenyl-N-(4-sulfamoylphenyl)propionamide was coupled smoothly with arenediazonium salt producing hydrazones which reacted with malononitrile or triethylorthoformate affording pyridazine and triazine derivatives, respectively. Also, the reactivity of the same precursor with DMF-DMA was followed by aminotriazole; aromatic aldehydes was followed by hydrazine hydrate, triethylorthoformate, or thiourea affording triazolo[1,5-a]pyrimidine, pyrazole, acrylamide, and dihydropyrimidine derivatives, respectively. On the other hand, treatment of the precursor propionamide with phenyl isothiocyanate and KOH in DMF afforded the intermediate salt which was treated with dilute HCl followed by 2-bromo-1-phenylethanone affording carboxamide derivative. While the same intermediate salt reacted in situ with chloroacetone, ethyl 2-chloroacetate, 3-(2-bromoacetyl)-2H-chromen-2-one, methyl iodide, or 2-oxo-N-phenylpropane hydrazonoyl chloride afforded the thiophene, ketene N,S-acetal, and thiadiazole derivatives, respectively. The structure of the new products was established based on elemental and spectral analysis. Antimicrobial evaluation of some selected examples from the synthesized products was carried out whereby four compounds were found to have moderate activities and one compound showed the highest activity.


N-
Yield ( (5). To a solution of the compound 3b (0.436 g, 1 mmol) in acetic acid (20 mL), triethyl orthoformate (0.2 mL, 1 mmol) was added and the reaction mixture was refluxed for 8 hrs; then it was left to cool.

4-(6-Phenyl
Yield (45%), m.p.  (13). To a stirred solution of potassium hydroxide (0.11 g, 1 mmol) in dimethylformamide (20 mL) the 1 (0.318 g, 1 mmol) was added. After stirring for 30 min, phenylisothiocyanate (0.27 g, 0.24 mL, 1 mmol) was added to the resulting mixture and stirring was continued for 6 h; then it was poured over crushed ice containing hydrochloric acid. The solid product formed was filtered off, washed with water, dried, and finally recrystallized from dioxane to afford 13.

Agar Diffusion Well
Method to Determine the Antimicrobial Activity. The microorganism inoculums were uniformly spread using sterile cotton swab on a sterile Petri dish malt extract agar (for fungi) and nutrient agar (for bacteria). One hundred L of each sample was added to each well (10 mm diameter holes cut in the agar gel, 20 mm apart from one another). The systems were incubated for 24-48 hours at 37 ∘ C (for bacteria) and at 28 ∘ C (for fungi). After incubation, the microorganism's growth was observed. Inhibition of the bacterial and fungal growth was measured in mm. Tests were performed in triplicate [31].

Results and Discussion
Heterocyclic azo compounds are well known for their use as antineoplastics [32], antidiabetics [33], antiseptics [34], and antibacterial activity [35] and are known to be involved in a number of biological reactions such as inhibition of DNA, RNA, protein synthesis, carcinogenesis, and nitrogen fixation [34][35][36]. Thus, propionamide 1 was coupled smoothly with diazonium salts, derived from the appropriate aromatic amines [4-methoxyaniline, 4-methylaniline, aniline, 4chloroaniline, and 4-nitroaniline) in pyridine, to afford the respective hydrazones 3a-e (Scheme 1). The structures of the products were established on the basis of their elemental analyses and spectral data (IR, 1 H NMR, and MS) [see Experimental Part]. In the 1 H NMR spectra of compounds 3a-e, absence of signal assignable to azomethine group (CH-N=N-) [37] at 3.00-4.00 ppm ruled out azo form and supported the hydrazone structure of the products.
Also, 1 reacts with aromatic aldehydes to afford the corresponding 2-benzoyl-3-aryl-2-yl-N-(4-sulfamoylphenyl)acrylamide derivatives 8a,b (Scheme 3). The IR spectrum of compound 8a, taken as a typical example, revealed absorption bands at 3349, 3255, and 1687 cm −1 corresponding to NH, NH 2, and CO functions, respectively. Its 1 H NMR spectrum showed signals at 8.48 and 9.14 corresponding to CH and NH protons in addition to aromatic protons at 7.46-7.94. Its mass spectrum showed a molecular ion peak at m/z 396. When the acrylamide derivative 8a was treated with hydrazine hydrate it afforded the corresponding pyrazole derivative 9a (Scheme 3). Spectroscopic data as well as elemental analyses of the obtained products were in complete agreement with the assigned structures 9a.
On the other hand, the reactivity of propionamide 1 towards triethylorthoformate and thiourea was investigated. Thus, condensation of 1 with triethylorthoformate in refluxing acetic anhydride afforded the ethoxy methylene derivative 10. Establishing of structure 10 was based on the elemental analysis and spectral data. Treatment of 1 with thiourea afforded the pyrimidine derivative 11. Establishing of compound 11 is based on its elemental analysis and spectral data (IR and 1 H NMR) (Scheme 3).

N-[4-(aminosulfonyl)phenyl]-2-anilino-4-phenyl-5-[(2-
oxo-2H-chromen-3-yl)carbonyl]thiophene-3-carboxamide (17). The reaction proceeds via nucleophilic displacement of bromide to give S-alkylated intermediate followed by loss of water of the latter intermediate to give thiophene derivatives 15 or 16 or 17 as the final products. The structures of the products 15-17 were determined from spectroscopic and elemental analytical data. Thus, compound 15, taken as a typical example, showed absorption bands at 3371, 3289, 3220, and 1636 cm −1 corresponding to NH, NH 2, and C=O groups, respectively. Its 1 H NMR spectrum revealed the absence of CH 2 protons of chloroacetone and showed signals at 9.46 and 9.88 due to 2NH protons, in addition to an aromatic multiplet in the region 7.13-7.63. The 13 C NMR of compound 15 revealed signals at 28.15, 162.59, and 189.30 for the carbons of the CH 3 of (COCH 3 ), CO of (CONH), and CO of (COCH 3 ) groups.
Furthermore, the nonisolated potassium salt was methylated by treatment with methyl iodide to afford the novel ketene N, S-acetal 18. The structure of the synthesized product was established on the basis of their elemental analysis and spectral data [see the Experimental Part].
Screening for Antimicrobial Activity. The newly synthesized compounds 3a, 3c, 6, 7, 8b, 10, 15, 16, and 17 were evaluated for their in vitro antibacterial activity against Staphylococcus aureus (RCMB-000106) (SA) and Bacillus subtilis (RCMB-000108) (BS) as examples of Gram-positive bacteria and Pseudomonas aeruginosa (RCMB-000102) (PA) and Escherichia coli (RCMB-000103) (EC) as examples of Gram-negative bacteria. They were also evaluated for their in vitro antifungal activity against Aspergillus fumigatus (RCMB-002003) (AF), Saccharomyces cerevisiae (RCMB-006002) (SC), and Candida albicans (RCMB-005002) (CA) fungal strains. Inhibition zone diameter (IZD) in mm was used as criterion for the antimicrobial activity using the agar diffusion well method. The fungicide clotrimazole and the bactericide streptomycin were used as references to evaluate the potency of the tested compounds under the same conditions. The results are depicted in Table 1. From the data given by Table 1 we concluded that most of the