Introduction

Despite many significant progresses in antimicrobial therapy, infectious diseases caused by bacteria and fungi remain a major worldwide health problem due to rapid development of resistance to the existing antimicrobial drugs (antibacterial and antifungal drugs). In other words, the increasing use and misuse of the existing antimicrobial drugs have resulted in the development of resistant pathogens (Berber et al., 2003; Appelbaum, 2006). So, the medical community faces a serious problem against infections caused by the pathogen bacteria and needs an effective therapy and search for novel antimicrobial agents.

Staphylococcus aureus, as example, has been recognized as an important pathogen of humans. Infections caused by this bacteria species can lead to serious consequences, especially in hospitalized patients. The appearance of methicillin-resistant strains of S. aureus (MRSA) has been a concern all over the world. This situation becomes worse and more threatening regarding the ease of transmission of the pathogen among individuals, resulting in the dissemination of MRSA (Gomes et al., 2006). The resistance to a great number of antibiotics presented by MRSA makes it difficult to control in hospital environments (Hiramatsu et al., 2002).

Considering the antimicrobial agents more recently approved for clinical use, a series of carboxamides, showed excellent in vitro and in vivo antibacterial activity present activity against Gram +ve organisms, including MRSA (Strigacova et al., 2000; Zanatta et al., 2007; Zhuravel et al., 2005). Carboxamides which contain -CONH- bridge connect the benzene or heterocyclic rings with antimycobacterial activity. This moiety can form centrosymmetric dimer pairs with the peptidic carboxamido group of some peptides, needed for binding to the receptor site, possibly by forming hydrogen bond (Matsuoka et al., 1999; Doležal et al., 2006).

In view of the scenario presented above, the search for new and effective antimicrobial agents, resistant to the mechanisms of defense of these bacteria, is of paramount importance.

As a part of our extensive research program to rapidly assemble novel bioactive heterocycles under mild conditions (Khalifa et al., 2013; Farag et al., 2012; Ismail et al., 2010; Ammar et al., 2006; Aly et al., 2010), we have employed naproxenoyl chloride (2) to prepare various new propionamide derivatives incorporating chiral carbon atom and also methoxy as lipophilic group to evaluate antimicrobial activity, hopefully, the new analogs with enhanced potency or of finding new applications. Various functional groups were introduced into the target compounds in order to investigate their preliminary structure activity relationships. The preceding functional groups have been suggested as being the pharmacophore responsible for the broad spectrum of biological activities shown by these moieties.

Results and discussion

Chemistry

The synthesis of the target compounds is depicted in Schemes 1, 2, and 3. The starting material, naproxenoyl chloride (2), was prepared through treatment of naproxen (1) with thionyl chloride (Al-Sehemi et al., 2006). This compound was proven to be a good synthons for different highly biologically active compounds. Thus, propionamide derivatives 3a–d were prepared via interaction of compound 2 with some aromatic amines. The structure of the products was characterized from their spectroscopic as well as elemental analytical data. For example, the IR spectrum of compound 3d revealed the absorption bands at: 3,386, 3,301, 1,651 cm−1 corresponding to two 2NH and C=O functions, respectively. 1H NMR spectrum of 3c showed signals at: 1.47, 3.45 corresponding to CH3 and CH2 protons and showed a quartet signal at: 3.97 due to the CH proton and two D2O exchangeable signals at 10.08 and 11.34 corresponding to NH and COOH protons. The sulfonamide functional group has a long and rich history in organic chemistry and drug discovery. Beginning with the discovery of the ‘sulfa’ antibiotics in the 1930s that revolutionized the treatment of bacterial infections, and continuing into the present day with the development of potent anti‐retrovirals used to treat patients infected with HIV, sulfonamides remain a particularly important class of compounds for the treatment of infectious diseases. Thus, condensation of the acid chloride 2 with some derivatives of sulfa drugs afforded the corresponding carboxamide derivatives 4a–c, Scheme 1. The analytical and spectral data were in agreement with the proposed structure. Thus, the 1H NMR spectrum of 4a showed a singlet at: δ = 1.88 for the CH3 of acetyl group and two singlets at: 9.85 and 10.56 singlet for two NH groups. Owing to the higher biological activity of amino acids, the authors planned to couple some of the amino acids with naproxene in one structure through an amide linkage. Hence, reaction of the naproxenoyl chloride with amino acids in the presence of pyridine furnished the amide derivatives 5a,b, Scheme 1. The structure of the isolated products was evidenced by its spectroscopic and elemental analysis data. Thus, IR spectrum of 5a exhibited absorption bands at: 3,380, 3,200–2,700, 1,740, 1,675 corresponding to NH, COOH, and two C=O groups. Moreover, its 1H NMR spectrum revealed signals corresponding to CH2 protons at: 3.72 and two D2O-exchangeable signals at: 8.25 and 12.55 corresponding to one NH and COOH. Further, the molecular ion peak recorded in the mass spectrum is also in agreement with the molecular weight of the compound.

Scheme 1
scheme 1

Synthesis of propionamide, sulfonamide, acyl aminoacid, bispropionamide and benzoimidazole derivatives

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Scheme 2
scheme 2

Synthesis of N-phenylacetamido and phenothiazine derivatives

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Scheme 3
scheme 3

Synthesis of oxazolone, acrylamide and 1,2,4-triazole derivatives

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Bis-compounds were reported to possess a wide range of biological activities. Thus, bis-naproxamide derivatives 6a–d were synthesized through interaction of two moles of the acid chloride derivative 2 with hydrazine hydrate, ethylenediamine, diethylenetriamine, and p-phenylenediamine, Scheme 1. Their structural assignment was secured via spectroscopic and microanalytical methods. Thus, the microanalyses were in satisfactory agreement with the calculated values (C, H, N values were within ±0.4 %). The mass spectra produced the desired molecular ion peaks with the appropriate isotopic distributions where applicable. Thus, the mass spectrum of compound 6d showed m/z at: 532 (M+) which is the base peak. Structures of the prepared compounds were further elucidated by the use of NMR and IR techniques. Thus, IR spectrum of product 6a revealed absorption bands at: 3,178 cm‐1 due to NH group, a band near 1,651 cm−1 that was attributed to the carbonyl group. 1H NMR spectrum of compound 6b revealed, besides an aromatic multiplet in the region of δ = 7.12–7.80 ppm, two singlet signals at: δ = 3.1, 8.1 attributed to CH2 and NH, respectively. The authors planned to couple naproxene moiety with biologically active heterocyclic compounds such as benzimidazole moiety. Thus, heating the acid chloride 2 with o-phenylenediamine in DMF under reflux affected cyclization to afford benzimidazole derivative 7. Structure 7 was suggested for this product based on analytical and spectral data. Thus, the IR spectrum revealed absorption bands at 3,225 and 1,608 due to (NH) and (C=N), respectively, and the absence of a band in the region of C=O group absorption. The 1H NMR spectrum revealed D2O exchangeable proton at 10.80 due to NH besides the ten aromatic protons in the region signals at: δ = 7.20–7.89; the mass spectrum of this product showed the molecular ion peak at m/z 302 (M+, 85.0) and base peak at 151 (100).

Now, we have extended our synthetic program to the synthesis of otherwise inaccessible ring system utilizing compound 3d as the key starting material. A mixture of 3d and acetyl chloride were reacted in dioxane under reflux condition in the presence of catalytic amounts of pyridine to yield a product which may be formulated as the acetyl derivative 8. The structure of acetyl derivative 8 was established from their IR, 1H NMR, and mass spectra. Its IR spectrum showed the presence of peaks at 3,280 due to NH group, in addition, for two bands in the region of 1,680, 1,670 corresponding to two carbonyl groups. 1H NMR spectrum showed two singlet signals at: 1.95, 10.2 due to CH3 acetyl and NH, and a multiplet signal in the region of 6.8–7.94 due to 15 aromatic protons. Mass spectrum showed molecular ion peak at: m/z 438 (M+) (29.13 %) with a base peak m/z 184. Also, upon treatment of compound 3d with sulfur and iodine in dichlorobenzene, the corresponding phenothiazine derivative 9 was obtained. Structure 9 was suggested for this product based on analytical and spectral data. The IR spectrum revealed absorption bands at: 3,312, 3,224 cm−1 (2NH), 1,650 cm−1 (C=O). 1H NMR spectrum revealed signals at: δ = 7.18–7.85 and 10.12, 12.13 ppm due to the aromatic and 2NH protons, respectively. (Scheme 2).

The authors planned to cover the coupling of naproxen moiety with different biologically active heterocyclic compounds such as oxazolone and triazole moieties.

Compound 5a was also used as a precursor for the synthesis of heterocyclic compounds. Thus, treatment of 5a with aromatic aldehydes in acetic anhydride containing catalytic amounts of sodium acetate under reflux afforded the oxazolone derivatives 10a–d, (Scheme 3). The structure of the obtained products was confirmed by their IR, NMR, and mass spectrum. The IR spectrum of compound 10a confirmed the formation of the lactone function through the presence of the carbonyl group at: 1,730. 1H NMR spectrum of compound 10c showed the presence of two singlet signals at: 2.32, 3.80 due to CH3 and OCH3, also the presence of doublet and quartet signals at: 1.48 and 3.9 corresponding to CH3 and CH besides multiplet signals at: δ = 7.13–7.88 ppm due to 11 aromatic protons. Mass spectrum of 10a exhibited a molecular ion peak at m/z 391 (M+: 8.4 %) with a base peak at: 197. The lactone function in the oxazolone ring was opened upon treatment of compound 10a with p-toluidine in ethanol under reflux, where the acrylic acid amide derivative 11 was obtained from Scheme 3. The IR spectrum showed absorption bands at 3,300 cm−1 (NH) and 1,675 cm−1 (C=O amide); 1HNMR showed two D2O exchangeable protons at: δ = 8.87 and 11.40 due to NH protons and a singlet signal at 2.23 due to CH3 group. In addition, compound 5a was allowed to react with either thiosemicarbazide or thio-carbohydrazide, where the triazole derivatives 12, 13 were obtained, respectively. Structure 13 was proved by its IR spectrum which revealed stretching frequencies of NH2 and NH at 3,400, 3,300 cm−1, and 1,221 (C=S). The 1H NMR for compound 13 showed three D2O exchangeable at: 5.56, 8.51, and 13.5 due to NH2, NH amide, and NH triazole, respectively, besides multiplet bands at δ = 7.13–7.82 ppm due to six aromatic protons.

Biological activity

Antibacterial activity

The synthesized compounds 3a–d, 4a–c, 5a, b, 6a, b, 8, 9, 10a, b, 11–13 (18 compounds) were tested in vitro for antibacterial activity against the following bacterial strains: Gram −ve bacteria, S. aureus RCMB 010027 and Bacillus subtilis RCMB 010063; and Gram-negative bacteria, Escherichia coli RCMB 000103 and Pseudomonas aeruginosa RCMB 010043. The results are summarized in Table 1. Antimicrobial tests were carried out by the agar well diffusion method (Scott, 1989) using 100 μl of tested compound solution prepared by dissolving 1 mg of the chemical compound in 1 ml of dimethyl sulfoxide (DMSO). The inoculated plates were then incubated for 24 h at 37 °C. The solution of Ampicilline (25 μg ml−1) was prepared in sterilized water and used as standards for comparison of antibacterial activity. After incubation time, antimicrobial activity was evaluated by measuring the inhibition zone diameters against the test organisms and compared with standard zone size ranges that determine susceptibility, intermediate susceptibility, or resistance to the screened compounds. Visual bacterial growth is observed only in areas in which the drug concentrations are below those required for growth inhibition. The experiment was carried out in triplicate, and the average zone of inhibition was calculated.

Table 1 Antimicrobial activity of the synthesized compounds against the pathological organisms expressed as inhibition diameter zones in millimeters (mm) based on well diffusion assay
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To obtain a clear picture about the structure activity relationship for the synthesized compounds, the target compounds were represented in general formula in Table 1. The mean values of inhibition zone diameters show that all tested compounds in the antibacterial assay possess significant activity against the growth of most test organisms.

The tabulated antimicrobial screening results of the tested compounds revealed that: Structure 3, Ar was aryl moiety (3a; 4-methylphenyl, 3b; 4-carboxyphenyl, 3c; 4-carboxymethylphenyl, 3d; 4-phenylaminophenyl): the presence of 4-carboxyphenyl moiety showed the maximum potent activities against the most tested organisms, 4-carboxyphenyl moiety showed result near to the reference drug against the two gram-negative bacteria: E. coli and P. aeruginosa. Other moieties showed moderate activity against the most tested organisms. Structure 4 has sulfonamide side chain ending with alkyl or aryl moieties; these moieties were acetyl; 4a, 5-methylisoxazol-3-yl; 4b, and 2-pyrimidinyl; 4c. The presence of pyrimidinyl moiety in 4c exhibited the highest antibacterial activity against most of the test organisms; pyrimidinyl moiety showed results equipotent to the reference drug against the most tested organisms. Also, 4a,b showed good activity against the most tested compounds. 4a,b showed strong activity against E. coli near to reference drug. Structure 5, Ar was CHRCOOH moiety (5a; R=H), 5b; R=CH3): all derivatives showed moderate activity against Staphylococcus aureus and B. subtilis, E. coli and no activities toward P. aeruginosa. Biscompounds 6a, b with two naphthyl and two amide moieties showed moderate activity against Staphylococcus aureus, B. subtilis and no activities toward P. aeruginosa. Structure 8 showed moderate activity against two Gram +ve bacteria, one Gram −ve bacteria (E coli) and showed no activity toward P. aeruginosa. Compound 9 with phenothiazine moiety showed strong activities against all of tested organisms. The activity was equipotent to the reference drug against the two Gram -ve bacteria. Structure 10 has oxazole side chain ending with chlorophenyl and fluorophenyl moieties. The presence of fluorophenyl moiety in case of 10b showed activity more than chlorophenyl moiety in case of 10a. Fluorophenyl moiety showed strong results against the most tested organisms. Compounds 12, 13, the aryl group have triazole moiety, showed good results against most of the test organisms. Compounds 12, 13 showed activity equipotent to the reference drug against E. coli and P. aeruginosa. The comparison between the antibacterial activities of our potent synthesized compounds and ciprofloxacin as standard antibacterial reference drug against the used Gram +ve and Gram-negative bacteria was represented graphically in Fig. 1.

Fig. 1
figure 1

The comparison between the antibacterial activities of our potent synthesized compounds and standard drug against the used Gram positive and Gram negative bacteria

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Antifungal activity

The search for newer antifungal agents continues due to the rapid development of the resistance among fungi to the existing antifungal agents. Even though novel broad spectrum antifungal agents were reported in recent years, the emergence of resistance has become an obstacle. Thus, more effective classes of such agents are desired. As such, propionamide derivatives may comprise a new class of antifungal agents. We chose Aspergillus ochraceus (RCMB 02593) and Candida albicans (RCMB 05035) in the antifungal susceptibility tests. Antifungal agents are evaluated against isolates of standard strains of fungi by the agar well diffusion method (Scott, 1989). The compounds were tested at a concentration of 1 mg ml−1 in DMSO solution. The solution of Flucanazole (25 μg ml−1) was prepared in sterilized water and used as standards for comparison of antifungal activity. The inoculated plates were then incubated for 72 h at 25 °C. After incubation time, antifungal activity was evaluated by measuring the inhibition zone against the test organisms and compared with that of the standard. Antifungal activities were expressed as inhibition zone diameter in millimeters (mm). The experiment was carried out in triplicate, and the average zone of inhibition was calculated. The results are tabulated in Table 1.

In general, some compounds were very effective antifungal agents and in several cases achieved similar or greater levels of activity as the standard antifungal agent Flucanazole (22 and 26 mm). It is noted, though, that some fluctuation in antibacterial activity for individual tested compounds was observed across the two strains of tested fungi. As anticipated, a clear difference in antifungal activity is noted between compounds within and between each series, pointing to the reinforcing and opposing effects of the Ar groups. The presence of 4-carboxyphenyl moiety in structure 3 showed the maximum potent activities against the test organism, 4-carboxyphenyl moiety showed result near to the reference drug against A. ochraceus. Other moieties showed moderate activity against the test organisms. For instance, compound 5a (Ar=CH2COOH) showed good activities against A. ochraceus (21 mm) and C. albicans (21 mm) related to the standard antifungal agent (21 and 26 mm). 10b, which has oxazole side chain ending with fluorophenyl moieties, showed good activity against the test fungi. Compounds 12, 13, the aryl group have triazole moiety and showed strong results near to the reference drug against A. ochraceus. Thus, these compounds comprise a promising new class of promising and potential broad spectrum antifungal agents. The comparison between the antifungal activities of our potent synthesized compounds and Flucanazole as standard antifungal drug against the used fungi is represented graphically in Fig. 2.

Fig. 2
figure 2

The comparison between the antifungal activities of our potent synthesized compounds and standard drug

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Minimum inhibitory concentrations against various tested strains

The minimum inhibitory concentration (MIC) is a standard technique used to measure the lowest concentration of a compound required to inhibit visible growth of a microorganism being investigated after approximately 24 h of incubation in the appropriate growth medium. MIC technique is a reliable means to determine the susceptibilities of microorganisms to drugs and also to monitor the activity of new ones. This technique provides a quantitative assessment of in vitro antimicrobial activity. Hence, further to the preceding tests of the potential antimicrobial and antifungal activities of synthesized compounds, we conducted a more quantitative assessment of the antimicrobial and antifungal activity of a narrow selection of potential leads by evaluating their minimum inhibitory. MIC values of the highest eight active synthesized compounds were measured by the procedure outlined in the Manual of Clinical Microbiology (Jones et al., 1984) against the same strains used earlier, and the results were reported in Table 2. As shown in Table 2, all compounds tested showed inhibitory effect, ranging from as low as 0.24 μg ml−1 to as high as 62.5 μg ml−1. In certain cases, such values are low enough to render such agents as potential candidates for further studies. Most of the tested compounds revealed MIC values lower than the standard against P. aeruginosa,, whereas compound 4c was consistently the most effective against all bacterial strains, producing the lowest MIC against test organisms. In relation to structure activity trends, the effect of the aryl moiety is much more discernible and dominant as clearly reflected in the significant disparity of MIC values obtained against a given strain for compound with a different aryl moiety.

Table 2 Minimum inhibitory concentration (μg ml−1) of the most potent synthesized compounds against the pathological organisms
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Conclusion

In conclusion, sulfonamide and triazoles containing (6-methoxy-naphthalen-2-yl)-propionamide which were easily prepared revealed promising antibacterial and antifungal activities. Thus, these compounds could be used as lead structure in pharmaceutical chemistry.

Experimental section

Melting points were determined on a digital Gallen-Kamp MFB-595 instrument and are uncorrected. IR spectra (KBr) were measured on a Shimadzu 440 spectrometer. 1HNMR and 13C spectra were recorded in deuterated dimethylsulfoxide (DMSO-d 6 ) on a Varian Gemini 300 (500 MHz) spectrometer using TMS as an internal standard; chemical shifts are reported as δ units. Mass spectra were performed on a Shimadzu GSMS-QP 1000 Ex mass spectrometer at 70 eV. The elemental analyses were carried out at the Microanalytical Center, Cairo University, Cairo (Egypt).

Synthesis of naproxenoyl chloride (2)

Naproxenoyl chloride was synthesized according to our reported procedure (Al-Sehemi et al., 2006) as follows: To a solution of naproxen (1) (0.01 mol) in m-xylene (30 ml), POCl3 (5 ml) was added. The reaction mixture was heated under reflux for 3 h, left to cool, the resulting precipitate was filtered off, washed with ether, and dried to give 2 as colorless crystals; mp 80–82 °C; Yield 75 %; 1H NMR: δ/ppm = 1.62 (d, 3H, J = 6.5 Hz, CH3), 3.84 (q, 1H, J = 6.5 Mz, CH), 3.94 (s, 3H, OCH3), 7.13–7.73 (m, 6H, Ar–H). 13C NMR: 18.24 (CH3), 45.21(CH), 55.32 (OCH3), 105.59 (C-5), 119.01 (C-7), 126.12 (C-4), 126.26 (C-8a), 127.21, 128.91, 129.31, 133.79, 135.16, 157.68, 179.27.

Synthesis of propionamides 3a–d

Equimolar amounts of naproxenoyl chloride (2) (0.01 mol) and the requisite amine (namely p-toluidine, 4-aminobenzoic acid, 2-(4-aminophenyl)acetic acid, and N1-phenylbenzene-1,4-diamine) (0.01 mol) in dioxane (20 ml) were treated with pyridine (0.5 ml). The reaction mixture was heated under reflux for 3 h. The solution was concentrated under vacuum, left to cool. The resulting solid was filtered off and recrystallized from ethanol.

2-(6-Methoxynaphthalen-2-yl)-N-(4-methylphenyl)-propionamide (3a)

Yield 70 %; mp 130–131 °C; IR: υ/cm−1 = 3,250 (NH), 3,039(CH–Ar), 2,979–2,932 (CH-sp3), 1,653(C=O); 1H NMR: δ/ppm = 1.56 (d, 3H, CH3), 2.34 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 3.90 (q, 1H, CH), 7.25–8.89 (m, 10H, Ar–H), 10.0 (s, 1H, NH); 13C NMR; 18.24 (CH3), 20.25 (CH3), 45.31(CH), 55.38 (OCH3), 105.76 (C-5), 119.21 (C-7), 120.42, 120.43, 126.25 (C-4), 126.27 (C-8a), 127.23, 128.94, 129.32, 129.53, 129.54, 133.24, 133.82, 135.16, 138.2, 157.67, 179.65; Anal. Calc. for C21H21NO2 (319.40): C, 78.97; H, 6.63; N, 4.39. Found: C, 78.80; H, 6.40; N, 4.20.

4-(2-(6-Methoxynaphthalen-2-yl)propanamido)benzoic acid (3b)

Yield 73 %; mp 235–236 °C; IR: υ/cm−1 = 3,278 (NH), 3,230–2,750 (broad COOH), 3,073(CH–Ar), 2,985–2,919 (CH-sp3), 1,700, 1,658(2C=O); 1H NMR: δ/ppm = 1.53 (d, 3H, CH3), 3.80 (s, 3H, OCH3), 3.86 (q, 1H, CH), 7.13–7.88 (m, 10H, Ar–H), 9.54, 11.25 (2s, 2H, NH + COOH); 13C-NMR: 18.35 (CH3), 45.23(CH), 55.38 (OCH3), 105.63 (C-5), 119.22 (C-7), 121.23, 121.25, 126.23 (C-4), 126.28 (C-8a), 126.89, 127.27, 128.87, 129.39, 130.12, 130.14, 133.87, 135.34, 137.23, 157.65, 173.32, 179.46; Anal. Calc. for C21H19NO4 (349.38): C, 72.19; H, 5.48; N, 4.01. Found: C, 72.30; H, 5.20; N, 4.20.

2-(4-(2-(6-Methoxynaphthalen-2-yl)propanamido)phenyl)acetic acid (3c)

Yield 68 %; mp 245–246 °C; IR: υ/cm−1 = 3,330, (NH), 3,250–2,750 (broad COOH), 3,070(CH–Ar), 2,970 (CH-sp3), 1,720, 1,660 (2C=O); 1H NMR: δ/ppm = 1.47 (d, 3H, CH3), 3.45 (s, 2H, CH2), 3.84 (s, 3H, OCH3), 3.97 (q,1H, CH), 7.10–7.80 (m, 10H, Ar–H), 10.08, 11.34 (2s, 2H, NH + COOH); 13C-NMR: 18.26 (CH3), 41.43 (CH2), 45.28(CH), 55.38 (OCH3), 105.46 (C-5), 119.21 (C-7), 120.86, 120.89, 126.23 (C-4), 126.36 (C-8a), 127.25, 128.87, 129.45, 130.12, 130.14, 131.34, 133.65, 135.34, 138.21, 157.76, 177.23, 179.34; Anal. Calc. for C22H21NO4 (363.41): C, 72.71; H, 5.82; N, 3.85. Found: C, 72.60; H, 5.50; N, 3.60.

2-(6-Methoxynaphthalen-2-yl)-N-(4-(phenylamino)phenyl)propanamide (3d)

Yield 70 %; mp 135–137 °C; IR: υ/cm−1 = 3,386, 3,301 (2NH), 3,062 (CH–Ar), 2,936 (CH-sp3), 1,651(C=O); 1H NMR: δ/ppm = 1.45 (d, 3H, CH3), 3.85 (s, 3H, OCH3), 3.95 (q, 1H, CH), 7.13–7.87 (m, 15H, Ar–H), 9.65, 10.45 (2s, 2H, 2NH); Anal. Calc. for C26H24N2O2 (396.48): C, 78.76; H, 6.10; N, 7.07. Found: C, 78.60; H, 6.30; N, 7.20.

Synthesis of sulfonamide derivatives 4a–c

A mixture of 2 (0.01 mol) and the appropriate sulfa drugs (namely sulfacetanilide, Sulfamethoxazole, and sulfadiazine) (0.01 mol) in dioxane (30 ml) was treated with pyridine (0.5 ml). The reaction mixture was heated under reflux for 3 h. The solution was concentrated under vacuum, left to cool. The resulting solid was filtered off and recrystallized from a mixture of ethanol/diaxone.

N-(4-(N-acetylsulfamoyl)phenyl)-2-(6-methoxynaphthalen-2-yl)propanamide (4a)

Yield 75 %; mp 230–231 °C; IR: υ/cm−1 = 3,325, 3,116 (2NH), 3,052(CH–Ar), 2,977 (CH-sp3), 1,710, 1,681(2C=O); 1H NMR: δ/ppm = 1.50 (d, 3H, CH3), 1.88 (s, 3H, COCH3), 3.87 (s, 3H, OCH3), 4.01(q, 1H, CH), 7.14–7.85(m, 10H, Ar–H), 9.85, 10.56 (2s, 2H, 2NH); 13C NMR: 16.56 (CH3), 18.34 (CH3), 45.43(CH), 55.42 (OCH3), 105.23 (C-5), 119.25 (C-7), 120.87, 120.88, 125.34, 125.35, 126.34 (C-4), 126.65 (C-8a), 127.35, 128.87, 129.24, 133.67, 135.12, 135.24, 142.54, 157.62, 174.54, 179.45; Anal. Calc. for C22H22N2O5S (426.49): C, 61.96; H, 5.20; N, 6.57. Found: C, 61.60; H, 5.30; N, 6.20.

2-(6-Methoxynaphthalen-2-yl)-N-(4-(N-(5-methylisoxazol-3-yl)sulfamoyl)phenyl)propanamide (4b)

Yield 80 %; mp 130–131 °C; IR: υ/cm−1 = 3,365, 3,254 (2NH), 3,087(CH–Ar), 2,937 (CH-sp3), 1,664 (C=O); 1H NMR: δ/ppm = 1.49(d, 3H, CH3), 2.43 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 3.94 (q, 1H, CH), 4.87 (s, 1H, CH-isoxazole), 7.15–7.77(m, 10H, Ar–H), 9.45, 10.32 (2s, 2H, 2NH); Anal. Calc. for C24H23N3O5S (465.52): C, 61.92; H, 4.98; N, 9.03. Found: C, 61.60; H, 4.70; N, 9.20.

2-(6-Methoxynaphthalen-2-yl)-N-(4-(N-pyrimidin-2-ylsulfamoyl)phenyl)propanamide (4c)

Yield 74 %; mp 175–176 °C; IR: υ/cm−1 = 3,350, 3,234 (2NH), 3,085(CH–Ar), 2,970 (CH-sp3), 1,680(C=O); 1H NMR: δ/ppm = 1.48(d, 3H, CH3), 3.87 (s, 3H, OCH3), 3.91 (q, 1H, CH), 7.23–8.32 (m, 13H, Ar–H), 9.32, 10.21 (2s, 2H, 2NH); Anal. Calc. for C24H22N4O4S (462.52): C, 62.32; H, 4.79; N, 12.11. Found: C, 62.40; H, 4.50; N, 12.20.

Synthesis of acyl aminoacid derivatives 5a, b

Equimolar amounts of naproxenoyl chloride (2) (0.01 mol) and the requisite aminoacids (namely glycine and alanine) (0.01 mol) in dioxane (20 ml) were treated with pyridine (0.5 ml). The reaction mixture was heated under reflux for 3 h. The solution was concentrated under vacuum, left to cool. The resulting solid was filtered off and recrystallized from ethanol.

2-(2-(6-Methoxynaphthalen-2-yl)propanamido)acetic acid (5a)

Yield 80 %; mp 125–126 °C; IR: υ/cm−1 = 3,380 (NH), 3,200–2,700 (COOH), 3,075(CH–Ar), 2,945 (CH-sp3), 1,740, 1,675(2C=O); 1H NMR: δ/ppm = 1.41 (d, 3H, CH3), 3.80 (s, 3H, OCH3), 3.86 (q, 1H, CH), 3.95 (d, 2H, CH2), 7.09–7.74 (m, 6H, Ar–H), 8.25 (s, 1H, NH), 12.5 (hump, 1H, NH); 13C NMR: 18.35 (CH3), 45.28(CH), 48.21 (CH2), 55.43 (OCH3), 105.63 (C-5), 119.28 (C-7), 126.39 (C-4), 126.48 (C-8a), 127.34, 128.89, 129.87, 133.84, 135.68, 157.69, 176.34, 179.64; MS, m/z (%): 287 (M+; 1.2), 257 (4.77), 243 (3.82), 213 (4.98), 199 (3.78), 185 (100), 154 (13.43), and 126 (7.76); Anal. Calc. for C16H17NO4 (287.31): C, 66.89; H, 5.96; N, 4.88. Found: C, 66.60; H, 5.70; N, 4.70.

2-(2-(6-Methoxynaphthalen-2-yl)propanamido)propanoic acid (5b)

Yield 65 %; mp 108–109 °C; IR: υ/cm−1 = 3,312 (NH), 3,200–2,750 (COOH), 3,076(CH–Ar), 2,954 (CH-sp3), 1,732, 1,665(2C=O); 1H NMR: δ/ppm = 1.42, 1.49 (2d, 6H, 2CH3), 3.87 (s, 3H, OCH3), 3.91, 4.23 (2q, 2H, 2CH), 7.13–7.67 (m, 6H, Ar–H), 8.92, 11.87 (2s, 2H, NH,COOH); 13C-NMR: 16.32 (CH3), 18.25 (CH3), 45.28(CH), 52.21 (CH), 55.43 (OCH3), 105.64 (C-5), 119.23 (C-7), 126.34 (C-4), 126.45 (C-8a), 127.24, 128.87, 129.54, 133.76, 135.61, 157.67, 176.34, 179.42; Anal. Calc. for C17H19NO4 (301.34): C, 67.76; H, 6.36; N, 4.65. Found: C, 66.80; H, 6.60; N, 4.70.

Synthesis of bispropionamide derivatives 6a–d

To a solution of the acid chloride 2 (0.01 mol) in dioxane (20 ml), hydrazine hydrate (0.012 mol) was added. In case of ethylenediamine, diethylenetriamine, or p-phenylenediamine (0.01 mol), pyridine (0.5 ml) was added. The reaction mixture was heated under reflux for 2 h. The solution was left to cool. The resulting solid was filtered off and recrystallized from dioxane.

2-(6-Methoxynaphthalen-2-yl)-N′-(2-(6-methoxynaphthalen-2-yl)propanoyl)propanehydrazide (6a)

Yield 72 %; mp 230–232 °C; IR: υ/cm−1 = 3,178 (NH), 3,066 (CH–Ar), 2,943 (CH-sp3), 1,654(C=O); 1H NMR: δ/ppm = 1.45 (d, 6H, 2CH3), 3.75 (s, 6H, 2OCH3), 3.88 (q, 2H, 2CH), 6.98–7.81 (m, 12H, Ar–H), 8.2 (s, 2H, 2NH); MS, m/z (%): 456 (M+; 2.32), 242 (0.32), 228 (1.12), 212 (100), 184 (13.75), 170 (22.8),128 (2.2); Anal. Calcd for C28H28N2O4 (456.53): C, 73.66; H, 6.18; N, 6.14. Found: C, 73.80; H, 6.30; N, 6.20.

N,N′-(ethane-1,2-diyl)bis(2-(6-methoxynaphthalen-2-yl)propanamide) (6b)

Yield 76 %; mp 200–202 °C; IR: υ/cm−1 = 3,294 (NH), 3,076 (CH–Ar), 2,939 (CH-sp3), 1,651(C=O); 1H NMR: δ/ppm = 1.37 (d, 6H, 2CH3), 3.1 (m, 4H, 2CH2), 3.67 (s, 6H, 2OCH3), 3.87 (q, 2H, 2CH), 7.12–7.80 (m, 12H, Ar–H), 8.1 (s, 2H, 2NH); MS, m/z (%): 484 (M+; 6.41), 300 (10.71), 255 (14.53), 242 (2.52), 228 (33.97), 212 (94.95), 184 (13.3), 171 (100), 100 (3.21); Anal. Calcd for C30H32N2O4 (484.59): C, 74.36; H, 6.66; N, 5.78. Found: C, 74.60; H, 6.40; N, 5.80.

N,N′-(2,2′-azanediylbis(ethane-2,1-diyl))bis(2-(6-methoxynaphthalen-2-yl)propanamide) (6c)

Yield 68 %; mp 220–222 °C; IR: υ/cm−1 = 3,317 (NH), 3,075 (CH–Ar), 2,939 (CH-sp3), 1,651(C=O); 1H NMR: δ/ppm = 1.29 (d, 6H, 2CH3), 3.0–3.14 (m, 8H, 4CH2), 3.76 (s, 6H, 2OCH3), 3.87 (q, 2H, 2CH), 7.12–7.81(m, 12H, Ar–H), 8.14, 9.18 (2 br, 3H, 3NH); Anal. Calcd for C32H37N3O4 (527.65): C, 72.84; H, 7.07; N, 7.96. Found: C, 72.50; H, 7.20; N, 7.80.

N,N′-(1,4-phenylene)bis(2-(6-methoxynaphthalen-2-yl)propanamide) (6d)

Yield 74 %; mp 260–262 °C; IR: υ/cm−1 = 3,302 (NH), 3,065 (CH–Ar), 2,943 (CH-sp3), 1,666(C=O); 1H NMR: δ/ppm = 1.48 (d, 6H, 2CH3), 3.87 (s, 6H, 2OCH3), 3.96 (q, 2H, 2CH), 7.13–7.83 (m, 16H, Ar–H), 10.06 (s, 2H, 2NH); MS, m/z (%): 532 (M+; 100), 347 (35.2), 333 (14.35), 199 (27.22), 182 (1.48),171 (13.71); Anal. Calcd for C34H32N2O4 (532.63): C, 76.67; H, 6.06; N, 5.26. Found: C, 77.50; H, 6.20; N, 5.40.

Synthesis of 2-(1-(6-methoxynaphthalen-2-yl)ethyl)-1H-benzo[d]imidazole (7)

A mixture of 2 (0.01 mol) and o-phenylenediamine (0.01 mol) in DMF (20 ml) was heated under reflux for 4 h. The solution was poured into ice-contained HCl, the obtained product was filtered and crystallized from ethanol: yield 67 %; mp 211-212 °C; IR: υ/cm−1 = 3,225 (NH), 3,065 (CH–Ar), 2,950 (CH-sp3), 1,608 (C=N); 1H NMR: δ/ppm = 1.56 (d, 3H, CH3), 3.77 (s, 3H, OCH3), 4.8 (q, 1H, CH), 7.20–7.89 (m, 10H, Ar–H), 10.80 (s, 1H, NH); MS, m/z (%): 302 (M+; 85), 256 (25), 227 (65), 184(71), 151 (100), 133 (78), 94 (82); Anal. Calcd for C20H18N2O (302.37): C, 79.44; H, 6.00; N, 9.26. Found: C, 79.50; H, 6.30; N, 9.40.

Synthesis of 2-(6-methoxynaphthalen-2-yl)-N-(4-(N-phenylacetamido)phenyl)propanamide (8)

A mixture of 3d (0.01 mol), acetyl chloride (0.02 mol), and pyridine (0.5 ml) in dioxane (20 ml) was heated under reflux for 4 h. The obtained product was filtered and crystallized from ethanol: yield 75 %; mp 180–182 °C; IR: υ/cm−1 = 3,280 (NH), 3,085 (CH–Ar), 2,950 (CH-sp3), 1,680, 1,670 (2C=O); 1H NMR: δ/ppm=1.59 (d, 3H, CH3), 1.95 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 4.00 (q, 1H, CH), 6.80–7.94 (m, 15H, Ar–H), 10.20 (s, 1H, NH); MS, m/z (%): 438 (M+; 29.13), 396 (51.46), 227 (61.49), 214 (61.34), 185(97.09), 184 (100), 154 (17.6),128 (7.12); Anal. Calcd for C28H26N2O3 (438.52): C, 76.69; H, 5.98; N, 6.39. Found: C, 76.50; H, 5.70; N, 6.40.

Synthesis of 2-(6-methoxynaphthalen-2-yl)-N-(4aH-phenothiazin-7-yl)propanamide (9)

A mixture of 3d (0.01 mol), sulfur metal and iodine (0.01 mol) in dichlorobenzene (20 ml) was heated under reflux for 6 h. The obtained product was filtered and crystallized from ethanol: yield 65 %; mp 305–306 °C; IR: υ/cm−1 = 3,312, 3,224 (2NH), 3,079 (CH–Ar), 2,940 (CH-sp3), 1,650 (C=O); 1H NMR: δ/ppm = 1.48 (d, 3H, CH3), 3.84 (s, 3H, OCH3), 3.92 (q, 1H, CH), 7.18–7.85 (m, 13H, Ar–H), 10.12, 12.13 (2s, 2H, 2NH); Anal. Calcd for C26H22N2O2S (426.53): C, 73.21; H, 5.20; N, 6.57. Found: C, 73.44; H, 5.45; N, 6.80.

Synthesis of oxazolone derivatives 10a–d

A solution of 5a (0.01 mol) in acetic anhydride (20 ml) was treated with the requisite aldehyde (0.01 ml) and fused sodium acetate (0.5 g). The reaction mixture was heated under reflux for 2 h. The obtained product was filtered and crystallized from ethanol:

4-(4-Chlorobenzylidene)-2-(1-(6-methoxynaphthalen-2-yl)ethyl)oxazol-5(4H)-one (10a)

Yield 72 %; mp 240–242 °C; IR: υ/cm−1 = 3,075 (CH–Ar), 2,950 (CH-sp3), 1,730 (C=O); 1H NMR: δ/ppm = 1.47 (d, 3H, CH3), 3.81 (s, 3H, OCH3), 3.90 (q, 1H, CH), 7.08–7.89 (m, 11H, Ar–H + CH=); MS, m/z (%): 391 (M+; 8.40), 227 (5.76), 197 (100), 181 (5.4), 154 (4.92), 127 (13.57); Anal. Calcd for C23H18ClNO3 (391.85): C, 70.50; H, 4.63; N, 3.57. Found: C, 70.40; H, 4.60; N, 3.70.

4-(4-Fluorobenzylidene)-2-(1-(6-methoxynaphthalen-2-yl)ethyl)oxazol-5(4H)-one (10b)

Yield 72 %; mp 190–192 °C; IR: υ/cm−1 = 3,072 (CH–Ar), 2,954 (CH-sp3), 1,727 (C=O); 1H NMR: δ/ppm = 1.46 (d, 3H, CH3), 3.84 (s, 3H, OCH3), 3.95 (q, 1H, CH), 7.1–7.84 (m, 11H, Ar–H + CH=); Anal. Calcd for C23H18FNO3 (375.39): C, 73.59; H, 4.83; N, 3.73. Found: C, 73.40; H, 4.60; N, 3.80.

2-(1-(6-Methoxynaphthalen-2-yl)ethyl)-4-(4-methylbenzylidene)oxazol-5(4H)-one (10c)

Yield 63 %; mp 180–182 °C; IR: υ/cm−1 = 3,071 (CH–Ar), 2,958 (CH-sp3), 1,732 (C=O); 1H NMR: δ/ppm = 1.48 (d, 3H, CH3), 2,32 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 3.90 (q, 1H, CH), 7.13–7.88 (m, 11H, Ar–H + CH=); Anal. Calcd for C24H21NO3 (371.43): C, 77.61; H, 5.70; N, 3.77. Found: C, 77.80; H, 5.50; N, 3.80.

4-(4-Methoxybenzylidene)-2-(1-(6-methoxynaphthalen-2-yl)ethyl)oxazol-5(4H)-one (10d)

Yield 64 %; mp 175–176 °C; IR: υ/cm−1 = 3,070 (CH–Ar), 2,958 (CH-sp3), 1,731 (C=O); 1H NMR: δ/ppm = 1.47 (d, 3H, CH3), 3.79, 3.82 (s, 6H, 2OCH3), 3.98 (q, 1H, CH), 7.14–7.88 (m, 11H, Ar–H + CH=); Anal. Calcd for C24H21NO4 (387.43): C, 74.4; H, 5.46; N, 3.62. Found: C, 74.50; H, 5.50; N, 3.80.

Synthesis of 3-(4-chlorophenyl)-2-(2-(6-methoxynaphthalen-2-yl)propanamido)-N-p-tolylacrylamide (11)

A solution of 10a (0.01 mol) in ethanol (30 ml) was treated with p-toluidine (0.01 ml). The reaction mixture was heated under reflux for 2 h. The obtained product was filtered and crystallized from ethanol: yield 64 %; mp 140–142 °C; IR: υ/cm−1 = 3,300 (NH), 3,069 (CH-Ar), 2,970 (CH-sp3), 1,675 (C=O); 1H NMR: δ/ppm = 1.49 (d, 3H, CH3), 2.23 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 3.93 (q, 1H, CH), 7.18–7.89 (m, 15H, Ar–H + CH=), 8.87 (s, 1H, 1NH); 11.4 (s, 1H, 1NH); Anal. Calcd for C30H27ClN2O3 (499.0): C, 72.21; H, 5.45; N, 5.61. Found: C, 72.40; H, 5.60; N, 5.70.

Synthesis of 1,2,4-triazoles 12 and 13

A mixture of 5a (0.01 mol) and thiosemicarbazide or thiocarbohydrazide (0.012 mol) was fused at 180 °C for 0.5 h. Left to cool, the solid product that remained was triturated with ethanol (20 ml), then filtered and crystallized from ethanol/dioxane.

2-(6-Methoxynaphthalen-2-yl)-N-((5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)propanamide (12)

Yield 62 %; mp 235–236 °C; IR: υ/cm−1 = 3,370, 3,300 (3NH), 3,071 (CH–Ar), 2,980 (CH-sp3), 1,650 (C=O), 1,223 C=S; Anal. Calcd for C17H18N4O2S (342.42): C, 59.63; H, 5.30; N, 16.36. Found: C, 59.40; H, 5.40; N, 16.50.

N-((4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-2-(6-methoxynaphthalen-2-yl)propanamide (13)

Yield 63 %; mp 190–192 °C; IR: υ/cm−1 = 3,400, 3,300 (NH2, NH), 3,069 (CH–Ar), 2,970 (CH-sp3), 1,656 (C=O), 1,221 C=S; 1H NMR: δ/ppm = 1.45 (d, 3H, CH3), 3.80 (s, 3H, OCH3), 3.90 (q, 1H, CH), 4.29–4.36 (m, 2H, CH2), 5.56 (s, 2H, NH2), 7.13–7.82 (m, 6H, Ar–H), 8.51 (s, 1H, NH), 13.5 (s, 2H, NH-triazole); 13C-NMR: 18.34 (CH3), 45.43 (CH), 46.21 (CH2), 55.54 (OCH3), 105.23 (C-5), 119.34 (C-7), 126.23 (C-4), 126.54 (C-8a), 127.234, 128.86, 129.45, 133.65, 135.23, 156.21, 158.20, 174.34, 187.23 (C=S); Anal. Calcd for C17H19N5O2S (357.43): C, 57.12; H, 5.36; N, 19.59. Found: C, 57.40; H, 5.60; N, 19.70.

Antimicrobial activity

Chemical compounds were individually tested against a panel of Gram +ve and gram-negative bacterial pathogens and fungi. Antimicrobial tests were carried out by the agar well diffusion method using 100 μl of suspension containing 1 × 108 CFU/ml of pathological tested bacteria and 1 × 106 CFU/ml of yeast spread on nutrient agar (NA) and Sabouraud dextrose agar (SDA) media, respectively. After the media had cooled and solidified, wells (10 mm in diameter) were made in the solidified agar and loaded with 100 μl of tested compound solution prepared by dissolving 1 mg of the chemical compound in 1 ml of dimethyl sulfoxide (DMSO). The inoculated plates were then incubated for 24 h at 37 °C. Negative controls were prepared using DMSO employed for dissolving the tested compound. After incubation time, antimicrobial activity was evaluated by measuring the zone of inhibition against the test organisms and compared with that of the standard. The observed zone of inhibition is presented in Table 1. Antimicrobial activities were expressed as inhibition diameter zones in millimeters (mm). The experiment was carried out in triplicate, and the average zone of inhibition was calculated.

Minimal inhibitory concentration (MIC) measurement

The bacteriostatic activity of the active compounds was then evaluated using the twofold serial dilution technique. Twofold serial dilutions of the tested compounds solutions were prepared using the proper nutrient broth. The final concentration of the solutions were 100, 50, 25, 12.5, and 6.25 μg ml−1. The tubes were then inoculated with the test organisms, grown in their suitable broth at 37 °C for 24 h for tested microorganisms (1 × 108 CFU/ml for bacteria and 1 × 106 CFU/ml of yeast), each 5 ml received 0.1 ml of the above inoculum and incubated at 37 °C for 24 h. The lowest concentration showing no growth was taken as the minimum inhibitory concentration (MIC).