Synthesis and Antimicrobial Activity of Chalcone-Derived 1,4-Dihydropyridine Derivatives Using Magnetic Fe₂O₃@SiO₂ as Highly Efficient Nanocatalyst

Abstract

The growing threat of bacterial resistance, coupled with the increasing costs associated with drug development, poses significant challenges in the discovery of new antibiotics. The present study reports the synthesis and antimicrobial evaluation of 1,4-dihydropyridine (1,4-DHP) derivatives derived from chalcones, using silica-mediated magnetic iron oxide, Fe₂O₃@SiO₂ nanoparticles as a nanocatalyst. The nanoparticles were characterized using FT-IR, SEM-EDS, XRD, Zeta-Potential, and VSM techniques to confirm their structure and properties. Among them, the series 8a–e (particularly compound 8c) demonstrated strong antimicrobial activity, with effectiveness comparable to standard drugs Fluconazole and Amoxicillin; this was attributed to the presence of polar groups. Other derivatives exhibited moderate activity, with MICs ranging from 25 to 50 μg/mL, while no significant activity was observed against Gram-negative bacteria. These compounds hold potential as promising antimicrobial agents and warrant further investigation for the development of effective therapies.

1. Introduction

The rapid advancements in drug development continue to captivate academia, the global economy, and the pharmaceutical sector [1]. In this dynamic landscape, contemporary multicomponent reactions (MCRs) have emerged as transformative tools, overcoming the limitations of conventional step-by-step synthesis [2]. MCRs enable highly selective, atom–economical reactions with unparalleled efficiency, offering significant advantages in the synthesis of pharmaceutical agents, antibiotics, and unique biological receptors [3,4]. To address the growing demand for innovative drug discovery, the strategic utilization of existing molecular scaffolds with inherent biological potential has become a priority [5]. These scaffolds serve as foundational frameworks for constructing novel molecular libraries, while adopting highly efficient synthetic strategies further accelerates progress in this critical area [6].

Among these scaffolds, chalcones have gained prominence due to their natural abundance, diverse biological activities, and versatility as precursors for complex heterocyclic transformations [7,8]. Naturally occurring chalcones, such as xanthohumol, isoliquiritigenin, and isobavachalcone, exhibit an extensive range of pharmacological properties, including anti-cancer, anti-inflammatory, antioxidant, anti-diabetic, anti-pigmentation, antimicrobial, and antibiotic effects [9,10]. Moreover, commercially available chalcone derivatives, such as metochalcone [11], sofalcone [12], and hesperidin methylchalcone [13], are widely used for their choleretic, anti-ulcer, and vascular protective properties. The chalcone framework has also been extensively explored for synthesizing derivatives such as pyrazolines, imidazoles, oxazolines, pyrimidines, and pyridines [14]. These synthetic endeavors have significantly enhanced the biological potential of chalcone derivatives, unlocking new therapeutic possibilities [15].

In contrast, 1,4-dihydropyridines (1,4-DHPs) have established themselves as pivotal bioactive compounds, renowned for their exceptional pharmaceutical profiles [16]. As the core structure in widely used drugs like nifedipine [17], amlodipine [18], nicardipine [15], and nimodipine [19], 1,4-DHPs are indispensable in treating hypertension and related cardiovascular conditions as calcium channel blockers [20]. Beyond this primary role, they exhibit a comprehensive field of biological activities, including anti-tumor, anti-inflammatory, anti-tubercular, anti-diabetic, antioxidant, anti-mutagenic, antibiotic, and antimicrobial effects [21]. Traditional synthesis approaches have long been employed for 1,4-DHPs synthesis, but they often suffer from limitations like prolonged reaction times, low yields, and limited selectivity [16,22]. Recent advancements have introduced innovative strategies to enhance efficiency, including the use of nanocatalysts (e.g., ferric oxide, nickel, tin dioxide, magnesium oxide) and advanced techniques such as microwave and ultrasonic-assisted methods [23,24]. Moreover, the synthesis of 1,4-dihydropyridines utilizing MnFe₂O₃ and nano-Fe₂O₃ nanoparticles as a catalyst provides high yields, selectivity, and purity, along with short reaction times and reusability, all under environmentally friendly conditions [25,26].

Interestingly, the convergence of biologically active chalcone scaffolds with the pursuit of 1,4-DHPs bearing hybrid properties holds immense promise [27]. This approach not only enriches the synthetic landscape but also unveils a captivating avenue for investigating their collective impact on biological attributes [28]. Building on our previous work with 1,4-DHPs and chalcone derivatives, we report the synthesis of 1,4-DHPs derived from chalcone frameworks. This approach marks a significant step toward designing innovative molecules with hybrid properties and expanded biological applications.

2. Result and Discussion

2.1. Synthesis of Fe₂O₃@SiO₂ Nanocatalyst

The Fe₂O₃ nanoparticles were created using the co-precipitation method based on our earlier research. We dissolved 12 g of FeCl₃ and 6 g of FeSO₄·7H₂O in 100 mL of deionized water, then purged the solution with N₂ gas and stirred it for 1 h. To adjust the pH to around 10, we added ammonia solution (25%) dropwise. The mixture was then heated to 70 °C while continuously stirring and purging with N₂ gas for 5 h, resulting in a black precipitate. Afterward, we filtered the precipitate, washed it with acetone and deionized water, and dried it in a vacuum oven at 60 °C. For the SiO₂ coating, we dissolved 3 g of TEOS in 50 mL of ethanol and added 1 mL of ammonium hydroxide for hydrolysis. We then dispersed 2 g of Fe₂O₃ nanoparticles in 100 mL of ethanol, mixed it with the SiO₂ sol, stirred for 4 h, filtered, washed with ethanol, and dried at 60 °C to obtain the Fe₂O₃@SiO₂ nanoparticles.

2.2. Characterization of Fe₂O₃@SiO₂ Nanoparticles

2.2.1. FT-IR Characterization

The FT-IR spectra of Fe₂O₃ and Fe₂O₃@SiO₂ nanoparticles, illustrated in Figure 1, revealed several characteristic differences in their functional groups, indicating successful silica coating on the Fe₂O₃ core. In the spectrum of Fe₂O₃, the characteristic peak at 796 and 552 cm⁻¹ attributes to Fe-O stretching vibrations, confirming the existence of iron oxide as the core material. However, the spectrum lacks any peaks associated with silica, as expected for pure Fe₂O₃. The adsorption band at 3464 cm⁻¹ corresponds to the O-H groups (stretching vibrations) present in the nanoparticles.

In the contrast, the spectrum of Fe₂O₃@SiO₂ nanoparticles displays additional peaks that signify the existence of silica. The absorption band observed at 544 cm⁻¹ is associated with the bending vibration mode of Fe₂O₃, providing further evidence of the iron oxide phase within the nanocomposite.

A prominent peak at 3396 cm⁻¹, along with another peak at 1629 cm⁻¹, corresponds to the bending vibrations of O-H groups, respectively, indicating the presence of adsorbed water molecules on the surface of the nanoparticles. These peaks confirm the hydrophilic nature of the material, which is a common feature of such nanostructures [29]. Moreover, the distinct band detected at 1061 cm⁻¹ corresponds to the antisymmetric stretching vibrations of Si-O-Si bonds, confirming the presence of silicon dioxide (SiO₂). This band is indicative of the SiO₂ shell that encapsulates the Fe₂O₃ core, forming the core–shell structure of the nanoparticles.

The combination of these characteristic peaks verifies the successful synthesis of Fe₂O₃@SiO₂ nanoparticles. The Fe₂O₃ core contributes to the redox properties essential for synthesis, while the SiO₂ shell ensures stability, prevents aggregation, and provides a large surface area for interaction with reactants.

2.2.2. DLS and Zeta-Potential Characterization

The Zeta-potential analysis of Fe₂O₃ and Fe₂O₃@SiO₂ nanoparticles reveals significant differences in their surface charge stability, as demonstrated in Figure 2a. The Fe₂O₃ nanoparticles exhibit a Zeta-potential value of −20.5 mV, indicating a moderately stable colloidal dispersion. In contrast, the Fe₂O₃@SiO₂ nanoparticles show an enhanced Zeta-potential of −32.8 mV, which is attributed to the silica coating. The silica shell introduces additional surface functional groups, which improve electrostatic repulsion between particles, thus enhancing their colloidal stability.

The Dynamic Light Scattering (DLS) analysis provides insight into the particle size and distribution, as demonstrated in Figure 2b. The Fe₂O₃ nanoparticles have a hydrodynamic diameter of 92.89 nm, while the silica coating increases the particle size to about 187.67 nm for Fe₂O₃@SiO₂. The increase in size is attributed to the formation of a uniform silica shell around the Fe₂O₃ core [30].

2.2.3. XRD Characterization

The crystalline structure of the Fe₂O₃@SiO₂ nanoparticles was examined via XRD analysis, utilizing Cu Kα radiation (λ = 1.54060 Å) with a scanning rate of 0.2 s over a range of 2θ = 20–70° and a step size of 10°. In the analysis of diffraction patterns, as shown in Figure 3, the peak observed at 30.25° was associated with the (110) crystallographic orientations of iron, indicating that the iron atoms in the sample were not fully oxidized. Further, other discernible peaks corresponding to the (012), (104), (110), (113), (024), and (116) crystallographic planes of a cubic structure of Fe₂O₃ were identified using standard data [31]. The formed XRD patterns correspond to the characteristic α-Fe2O3 pattern (JCPDS No. 33-0664). Additionally, a peak attributed to SiO₂ with (011) crystallographic orientations was evident in the figure. With the crystallite size estimated at approximately 30 nm, it can be concluded that the Fe₂O₃@SiO₂ nanoparticles exhibit a nano-crystalline structure [32].

The XRD characterization of Fe₂O₃@SiO₂ nanoparticles reveals valuable information about their crystalline structure and phase composition. The diffraction pattern shows sharp peaks corresponding to the (012), (104), (110), (113), (024), and (116) crystalline phases of Fe₂O₃, specifically the hematite phase, which confirms the successful synthesis of iron oxide nanoparticles with a well-ordered crystalline structure. In addition, the broad hump observed in the 20–30° 2θ region indicates the presence of amorphous silica (SiO₂), which is characteristic of silica prepared through sol–gel or similar methods [33]. This confirms that the SiO₂ coating on the Fe₂O₃ nanoparticles is non-crystalline, forming an amorphous shell around the crystalline core. The coexistence of crystalline Fe₂O₃ and amorphous SiO₂ phases validates the successful formation of Fe₂O₃@SiO₂ core–shell nanoparticles. This core–shell structure not only enhances the material’s stability but also broadens its functional applications in areas such as catalysis, adsorption, and environmental remediation.

2.2.4. SEM-EDS Characterization

The SEM images, as shown in Figure 4a–f, provide a comparative morphological analysis of Fe₂O₃ and Fe₂O₃@SiO₂ nanoparticles, offering insights into the uniformity and distribution of the nanoparticles, as well as the presence of agglomeration.

The SEM images presented show the morphology and surface structure of Fe₂O₃ and Fe₂O₃@SiO₂ nanoparticles at different magnifications. Figure 4a shows Fe₂O₃ nanoparticles displaying an aggregated structure with irregularly shaped particles. The particles appear loosely packed, with a rough and uneven surface, indicating their potential for high surface reactivity. The particle size distribution varies, as seen from different scale bars (5 μm, 10 μm, and 20 μm), suggesting a heterogeneous morphology.

In contrast, Figure 4d–f represent Fe₂O₃@SiO₂ nanoparticles, revealing a distinctly different structure. The presence of SiO₂ coating is evident from the formation of a more structured and porous network. Figure 4d highlights the intricate porous structure with a well-defined texture, which could enhance the surface area and catalytic activity. Figure 4e further illustrates the hierarchical porosity, where layered formations and interconnected voids are visible, promoting better adsorption and reactant diffusion. Figure 4f provides an overall view of the Fe₂O₃@SiO₂ composite, showing a dispersed, structured morphology with significantly reduced aggregation compared to pure Fe₂O₃ [34].

These structural transformations indicate that the SiO₂ coating not only stabilizes Fe₂O₃ nanoparticles but also introduces hierarchical porosity, which is beneficial for the catalytic applications. The improved dispersion and increased surface area are expected to enhance the performance of Fe₂O₃@SiO₂ nanoparticles in various chemical reactions.

The EDS (Energy-Dispersive Spectroscopy) analysis of Fe₂O₃@SiO₂ nanoparticles, obtained through elemental mapping, confirms the presence of iron (Fe), oxygen (O), and silicon (Si) in the sample, indicating the successful synthesis of the composite. Iron was detected with a mass percentage of 25.95 ± 1.51% and an atomic percentage of 35.77 ± 2.08%, suggesting the presence of iron in Fe₂O₃ nanoparticles. Oxygen, with the highest atomic percentage of 47.81 ± 2.35% and a mass percentage of 46.20 ± 2.27%, highlights its critical role in the oxides (SiO₂ and Fe₂O₃) and ensures the stability of the nanocomposite structure. Silicon, derived from the SiO₂ shell, was observed with a mass percentage of 27.86 ± 1.42% and an atomic percentage of 16.42 ± 0.84%, confirming the effective coating of Fe₂O₃ nanoparticles. Also, based on the EDS data, the Fe₂O₃:SiO₂ mass ratio is 0.6:1, indicating a higher proportion of SiO₂ in the composite. The EDS data verify the successful incorporation of SiO₂ into the composite and confirm the expected elemental composition, demonstrating the effectiveness of the synthesis process [29].

2.2.5. VSM Characterization

The magnetization hysteresis loop of both Fe₂O₃ as well as Fe₂O₃@SiO₂ nanoparticles, as depicted in Figure 5, provides valuable insights into their magnetic behavior. The saturation magnetization (Ms) of Fe₂O₃ nanoparticles is 69.5 emu/g, reflecting their strong ferrimagnetic nature, which makes them suitable for applications requiring high magnetic responsiveness, such as magnetic separation and biomedical uses. However, upon coating with SiO₂, the M_s of Fe₂O₃@SiO₂ nanoparticles decreases significantly to 46.8 emu/g. This decrease is attributed to the non-magnetic nature of the SiO₂ shell, which dilutes the overall magnetic moment of the composite. The SiO₂ layer acts as a barrier, reducing the magnetic interaction between Fe₂O₃ particles and decreasing their effective magnetization [35].

Furthermore, the SiO₂ coating enhances the stability of the nanoparticles by protecting the Fe₂O₃ core from oxidation and preventing agglomeration, which is a critical factor in maintaining their functional properties in various applications. Despite the reduction in M_s, the Fe₂O₃@SiO₂ nanoparticles retain sufficient magnetic properties for practical use while gaining improved stability and dispersibility. This balance between reduced magnetization and enhanced functionality underscores the potential of Fe₂O₃@SiO₂ nanoparticles in fields such as catalysis, environmental remediation, and biomedical applications.

2.3. Optimization of Conditions for Synthesis of Chalcone-Derived 1,4-Dihydropyridine Derivative

The chalcone-derived 1,4-DHPs derivatives were synthesized by condensation of an active methylene compound 4a–e with a chalcone derivative 3a–c in the presence of ammonium acetate 5, and the synthetic route to synthesize compounds 6a–e, 7a–e, and 8a–e. A model condensation reaction was established to optimize the reaction conditions, containing a solution of chalcone 3a–c (1 mmol), methyl-3-oxobutanoate 4a (1 mmol, 0.116 g), and NH₄OAc 5 (1 mmol, 0.077 g) in 5 mL of ethanol, microwave-irradiated at 80 watts.

2.3.1. Optimization of Amount of Fe₂O₃@SiO₂ Nanocatalyst

The effect of the Fe₂O₃@SiO₂ nanocatalyst amount on the model reaction was thoroughly investigated to optimize the 1,4-DHPs derivatives synthesis (6a, 7a, and 8a) in terms of yield and reaction time. The results (

Table 1. Optimizing the amount of Fe₂O₃@SiO₂ nanocatalyst on model reaction.

Entry	Fe2O3@SiO2 (mmol%)	Time (minutes)	Yield of 6a a,* (%)	Yield of 7a a,* (%)	Yield of 8a a,* (%)
1	0	10	51	49	54
2	1	8	74	72	70
3	2	7	89	85	87
4	3	6	93	92	94
5	3	8	91	90	91
6	3	10	90	89	90
7	4	6	92	91	94
8	5	6	92	92	93

^a Yield refer to extraction of all crops. * Reaction conditions: chalcone (1 mmol), methyl-3-oxobutnoate (1 mmol, 0.116 g), ammonium acetate (1 mmol, 0.077 g), and ethanol (5 mL) at 80 watts.

) demonstrate that the nanocatalyst amount significantly impacts both the reaction rate and product yields. Without the catalyst (Entry 1), the reaction proceeded slowly, resulting in yields of 51%, 49%, and 54% for 6a, 7a, and 8a, respectively, after 10 min. When using pure Fe₂O₃ (Entry 6) as the catalyst at 3 mmol%, the reaction yielded 66%, 63%, and 62% for 6a, 7a, and 8a, respectively, in 10 min. While this demonstrates some catalytic activity, the lower yields compared to Fe₂O₃@SiO₂ suggest that the SiO₂ coating enhances catalytic efficiency, likely by improving dispersion, increasing surface area, or modifying the electronic environment of the active sites.

As the catalyst amount increased to 2 mmol% (Entry 3), yields further improved to 89%, 85%, and 87%, and the reaction time reduced to 7 min. The optimal performance was observed at 3 mmol% of the catalyst (Entry 4), where yields of 93%, 92%, and 94% were achieved in just 6 min. Increasing the catalyst amount to 4 mmol% (Entry 5) did not provide any significant improvement, with yields of 92%, 91%, and 94% matching closely with those at 3 mmol%.

However, increasing the catalyst loading to 5 mmol% (Entry 8) did not significantly enhance the yield but maintained a high conversion rate (92–93%), indicating that an excess of catalyst beyond a certain threshold does not provide substantial benefits. A comparison with Entries 5 and 6, where the catalyst amount remained at 3 mmol% but the reaction time was extended to 8 and 10 min, respectively, shows a gradual decline in yield. At 8 min (Entry 5), the yield dropped slightly (91% for 6a, 90% for 7a, and 91% for 8a), and at 10 min (Entry 6), a further decrease was observed (90% for 6a, 89% for 7a, and 90% for 8a).

These results highlight the importance of optimizing both catalyst loading and reaction time. While a longer reaction time generally allows for higher conversion, excessive durations may lead to secondary reactions or catalyst deactivation, slightly reducing the yield. Additionally, excessive catalyst amounts may not necessarily improve efficiency, as observed in Entry 8. Therefore, the best balance between reaction time and catalyst amount appears to be 3 mmol% Fe₂O₃@SiO₂ with a reaction time of 6 min, ensuring high product yields with minimal reaction time [36].

2.3.2. Optimization of Solvent

The solvent plays a crucial role in the efficiency, yield, and reaction time of the condensation reaction catalyzed by 3 mmol% Fe₂O₃@SiO₂ nanocatalyst for synthesizing 1,4-DHPs derivatives, i.e., 6a, 7a, and 8a. A range of solvents were assessed under standardized reaction conditions, and the results are summarized in

Table 2. Optimization of solvent for 1,4-DHPs derivatives synthesis, i.e., 6a, 7a, and 8a.

Entry	Solvent	Time (Minutes)	Yield of 6a a,* (%)	Yield of 7a a,* (%)	Yield of 8a a,* (%)
1	Polyethylene glycol	20	70	68	69
2	Ethylene glycol	20	72	74	73
3	Water	15	35	36	38
4	Acetonitrile	14	70	72	68
5	Glycerol	15	90	91	89
6	Ethanol	7	94	95	93
7	Methanol	11	82	80	84
8	DMSO	30	30	32	34
9	DMF	25	55	55	56
10	No solvent	30	-	-	-

^a Yield refers to extraction of all crops. * Reaction conditions: chalcone (1 mmol), methyl-3-oxobutanoate (1 mmol, 0.116 g), ammonium acetate (1 mmol, 0.077 g), and Fe₂O₃@SiO₂ nanocatalyst (3 mmol%) at 80 watts.

. The choice of solvent significantly influences the efficiency, yield, and reaction time of the condensation reaction catalyzed by 3 mmol% Fe₂O₃@SiO₂ nanocatalyst for synthesizing 1,4-DHPs derivatives (6a, 7a, and 8a). A variety of solvents (5 mL) were evaluated under standardized reaction conditions, and the findings are presented in Table 2.

Ethanol was identified as the optimal solvent (Table 2, Entry 6), delivering an exceptional yield of 94–95% within just 7 min. This superior performance can be attributed to ethanol’s excellent solvating ability, which enhances the dissolution of reactants and facilitates efficient molecular interactions [37]. Glycerol (Entry 5) also demonstrated high efficiency, yielding 90–91%, but required a longer reaction time of 15 min, possibly due to its higher viscosity, which may slow diffusion rates [38]. In the absence of a solvent (Entry 11), no product was obtained, likely due to poor reactant mobility and inadequate catalyst dispersion, which prevented effective interaction between the reacting species.

In contrast, solvents like methanol and acetonitrile provided moderate yields with longer reaction times (Entries 4 and 7), while water (Entry 3), DMSO (Entry 8), and DMF (Entry 9) were less effective, likely due to poor compatibility with the reactants or reduced catalytic activity in these media. These results highlight ethanol’s unique suitability for achieving high yields in minimal reaction time. Moreover, when the amount of ethanol was reduced from 5 mL to 1 mL, the reaction did not proceed, likely due to insufficient solubilization of the reactants and inadequate dispersion of the catalyst, which hindered proper interaction between the reacting species. This observation suggests that ethanol not only acts as a solvent but may also play a crucial role in stabilizing intermediates or enhancing the catalytic efficiency, making it the optimal choice for this transformation.

2.3.3. Optimization of Microwave Reactor Power

The influence of microwave power levels on the synthesis of 1,4-DHPs derivatives (6a, 7a, and 8a) was systematically investigated, and the results are presented in

Table 3. The impact of power levels of microwave reactor for the synthesis of 1,4-DHPs derivatives.

Entry	Watts	Time (minutes)	Yield of 6a a,* (%)	Yield of 7a a,* (%)	Yield of 8a a,* (%)
1	75	15	79	77	80
2	80	12	81	80	82
3	85	7	92	91	90
4	90	4	98	96	98
5	95	4	96	97	95
6	100	5	93	91	92

^a Yield refer to extraction of all crops. * Reaction conditions: chalcone (1 mmol), methyl-3-oxobutanoate (1 mmol, 0.116 g), ammonium acetate (1 mmol, 0.077 g), Fe₂O₃@SiO₂ nanocatalyst (3 mmol%), and ethanol (5 mL).

. The study demonstrates a clear relationship between power levels and reaction efficiency, particularly in terms of yield and reaction time. At lower power levels (75–85 W), the reaction proceeded more slowly, with yields reaching up to 92% at 85 W within 7 min (Table 3, Entry 3). This indicates that lower energy input is insufficient to maximize the interaction between reactants and the catalyst within a shorter time frame.

The maximum yield of 98% was achieved at 90 W in just 4 min (Table 3, Entry 4), highlighting this power level as the most efficient. The enhanced energy density at 90 W ensures optimal activation of reactants, leading to faster reaction rates and higher yields. However, increasing the power beyond 90 W (95–100 W) resulted in a slight decline in yield, with 96% and 93% recorded at 95 W and 100 W, respectively (Table 3, Entries 5 and 6). This reduction is likely due to the decomposition of intermediates or the product caused by excessive energy input.

Therefore, the optimal microwave power level for this reaction is identified as 90 W, which balances efficiency, yield, and reaction time. This demonstrates the importance of precise power control in microwave-assisted synthesis to achieve maximum product efficiency.

2.3.4. Reusability of Fe₂O₃@SiO₂ Nanocatalyst

The reusability study of the Fe₂O₃@SiO₂ nanocatalyst under optimized conditions confirmed its exceptional stability and efficiency, with consistently high product yields over four consecutive cycles, as shown in

Table 4. Reusability of Fe₂O₃@SiO₂ nanocatalyst for 1,4-DHPs derivatives synthesis.

Entry	Run	Yield for 6a a,* (%)	Yield for 7a a,* (%)	Yield for 8a a,* (%)
1	Fresh	98	96	98
2	1	97	95	97
3	2	97	94	96
4	3	96	94	96
5	4	95	93	95

^a Yield refers to extraction of all crops. * Reaction conditions: chalcone (1 mmol), methyl-3-oxobutanoate (1 mmol, 0.116 g), ammonium acetate (1 mmol, 0.077 g), Fe₂O₃@SiO₂ nanocatalyst (3 mmol%), and ethanol (5 mL).

. The fresh catalyst achieved a yield of 98%, which gradually decreased to 95% by the fourth run. This minor reduction in catalytic activity can be attributed to the potential loss of active sites due to minor leaching of the catalyst or the accumulation of by-products on the surface during repeated use.

This stability is attributed to the robust structure of the nanocatalyst, where SiO₂ provides a protective framework for Fe₂O₃, ensuring its active sites remain effective. The marginal decline in yield may result from minor physical wear or loss of catalyst during recovery and washing. The excellent recyclability of the nanocatalyst enhances the economic viability and aligns with sustainable green chemistry practices, making it a practical choice for repeated use in organic synthesis.

2.4. Characterization of Methyl-2-methyl-4,6-diphenyl-1,4-dihydropyridine-3-carboxylate (6a)

The compound methyl 2-methyl-4,6-diphenyl-1,4-dihydropyridine-3-carboxylate (6a) was obtained as a white crystalline solid with a melting point of 156–157 °C. In its IR spectrum, the broad peak at 3441 cm⁻¹ indicates N-H stretching, confirming the presence of a secondary amine group. The aromatic C-H stretching vibrations appear at 3106 cm⁻¹, while the methyl C-H stretching is observed at 2943 cm⁻¹. A sharp band at 3031 cm⁻¹ suggested the presence of a carboxyl group (-COOH). The strong band at 1668 cm⁻¹ corresponds to the carbonyl (C=O) stretching, which is characteristic of an ester group. The C=C stretching vibrations of the aromatic ring are observed at 1595 cm⁻¹. Additionally, peaks at 1206 cm⁻¹ and 1081 cm⁻¹ are associated with C-O stretching, indicating the presence of ester and methoxy groups. These spectral features collectively confirm the structural integrity and functional groups of the synthesized compound.

The ¹H NMR spectrum, the aromatic region displays two sets of signals corresponding to the phenyl rings. The multiplet at δ 8.01–7.47 ppm (10H) is attributed to the protons of two phenyl rings. The singlet at δ 11.13 ppm (1H) is due to the N-H proton of the dihydropyridine ring. The protons of the dihydropyridine ring resonate at δ 4.72–4.71 ppm (1H) and δ 4.35–4.32 ppm (1H), reflecting the fact that they are chemically and magnetically inequivalent. The methoxy group appears as a singlet at δ 3.54 ppm (3H), while the methyl group attached to the dihydropyridine ring is observed as a singlet at δ 2.26 ppm (3H).

In the ¹³C NMR spectrum, the carbonyl carbon of the ester group resonates at δ 173.2 ppm, confirming the presence of the C=O functional group. The aromatic carbons are distributed over several peaks, with δ 151.6 ppm corresponding to C-2 (of the dihydropyridine ring), and δ 142.4 ppm and δ 141.7 ppm representing C-1’ and C-6, respectively. The remaining aromatic carbons appear between δ 135.1 ppm and δ 126.4 ppm, corresponding to the phenyl rings. The C=C bond of the dihydropyridine ring resonates at δ 124.9 ppm. The C-3 and C-5 carbons of the dihydropyridine ring are observed at δ 106.8 ppm and δ 94.5 ppm, respectively, while C-4 resonates at δ 47.6 ppm. The methoxy group carbon (COOCH₃) is evident at δ 55.1 ppm, and the methyl carbon (CH₃) attached to the dihydropyridine ring appears at δ 19.2 ppm. These data collectively validate the successful synthesis and characterization of compound 6a. The mass spectrum displayed a molecular ion peak at m/z 306 [M + 1], consistent with the molecular formula C₂₀H₁₉NO₂. Elemental analysis also supported the compound’s composition, with calculated and observed values closely matching for carbon, hydrogen, and nitrogen. These data collectively validate the successful synthesis and characterization of compound 6a.

Table 5. Comparison of synthesis time, yield, and melting points of chalcone-derived 1,4-dihydropyridine derivatives.

Entry	Chalcone-Derived 1,4-DHPs Derivatives	Rf	Yield (%)	Melting Point (°C)		Reference
				Lit	Exp
1	6a	0.78	94	153–155	156–157	[13]
2	6b	0.79	92	162–164	164–166	[20]
3	6c	0.75	96	270–271	271–272	[13]
4	6d	0.73	93	260–261	263–265	[28]
5	6e	0.71	95	202–203	204–205	[28]
6	7a	0.66	94	131–133	133–134	[13]
7	7b	0.67	97	150–152	151–153	[20]
8	7c	0.64	92	239–240	239–241	[28]
9	7d	0.63	91	234–235	236–238	[20]
10	7e	0.62	94	210–211	202–204	[28]
11	8a	0.67	90	170–171	172–173	[20]
12	8b	0.68	93	185–187	187–188	[13]
13	8c	0.62	95	284–286	286–288	[28]
14	8d	0.61	96	288–290	289–291	[20]
15	8e	0.59	93	212–214	215–216	[20]

provides an overview of the synthesis and characterization of chalcone-derived 1,4-dihydropyridine derivatives (6a–e, 7a–e, and 8a–e), detailing their reaction times, yields, and melting points.

Figure 6 illustrates the structures of chalcones and chalcone-derived 1,4-dihydropyridine derivatives (6a–e, 7a–e, 8a–e), highlighting their key modifications. All these derivatives were synthesized efficiently with reaction times ranging between 3 and 5 min and yields exceeding 90%, showcasing the effectiveness of the method. The observed melting points closely align with the reported literature values, confirming the successful synthesis and high purity of the compounds. These results underscore the reproducibility and efficiency of the synthetic approach employed for these derivatives.

2.5. Plausible Mechanism for Synthesis of Chalcone-Derived 1,4-Dihydropyridine Derivatives

The synthesis of chalcone-derived 1,4-dihydropyridine derivatives, using Fe₂O₃@SiO₂ as a nanocatalyst, follows a series of well-defined steps that are catalytically enhanced by the Fe₂O₃@SiO₂ nanomaterial. This core–shell nanocatalyst accelerates the reaction by providing active sites for adsorption and activation of reactants, facilitating electron transfer, and stabilizing key intermediates [39]. The Fe₂O₃ core, known for its Lewis acidity, facilitates the activation of the chalcone carbonyl group by coordinating with oxygen and stabilizing key intermediates, thereby enhancing the reaction efficiency. The SiO₂ shell prevents nanoparticle aggregation and maintains consistent catalytic activity, ensuring that the catalysts can be reused for multiple cycles [40]. The Fe₂O₃@SiO₂ nanocatalyst provides a large surface area for the adsorption and activation of the chalcone 3 and active methylene compound, 4. The iron oxide core facilitates electron transfer, enhancing the electrophilicity of the chalcone carbonyl group. Their surface contains active sites that facilitate the activation of reactants and intermediates by coordinating with functional groups [41].

Ammonium acetate 5 reacts with the β-ketoester 4 in the presence of magnetic nanoparticles. The nanoparticles likely activate the carbonyl group of the β-ketoester, making it more electrophilic [42]. Ammonium acetate donates ammonia, which undergoes nucleophilic attack to form an enamine intermediate I, as shown in Scheme 1. The chalcone (α, β-unsaturated ketone) reacts with the enamine intermediate I. Magnetic nanoparticles stabilize this reaction by activating the electrophilic β-carbon of the chalcone 3 [43]. The nucleophilic enamine attacks this β-carbon, leading to a Michael-type addition and forming a new intermediate II. The intermediate undergoes intramolecular cyclization. The carbonyl oxygen from the β-ketoester forms a bond with the nearby nucleophilic amine group. The magnetic nanoparticles assist in this step by stabilizing the transition state, ensuring smooth cyclization.

The magnetic nanoparticles further catalyze the dehydration process, facilitating the removal of a water molecule, thereby driving the reaction to completion and yielding the final product. Magnetic nanoparticles ensure high selectivity and efficiency by stabilizing reactive intermediates throughout the process [44].

This mechanism highlights the synergistic role of the Fe₂O₃@SiO₂ nanocatalyst, where the Fe₂O₃ core drives electron transfer and redox processes, while the SiO₂ shell ensures catalyst stability and high efficiency throughout the reaction. The reaction under these conditions offers a green and efficient method for synthesizing chalcone-derived 1,4-dihydropyridine derivatives [45].

2.6. Antimicrobial Activity

The antimicrobial activity of the synthesized compounds (6a–e, 7a–e, and 8a–e) was evaluated against selected microbial strains using the Minimum Inhibitory Concentration (MIC) method, with the results summarized in

Table 6. The antimicrobial activity of chalcone-derived 1,4-dihydropyridine derivatives (6a–e, 7a–e, and 8a–e).

Chalcone-Derived 1,4-DPHs Derivatives	Gram (+ve) Bacteria		Gram (-ve) Bacteria			Fungi
	B. Subtilis	S. Pyogenes	E. Coli	K. Pneumonia	S. Aureus	A. Janus	A. Niger	A. Sclerotiorum
6a	128	46	64	128	32	64	128	–
6b	128	64	64	32	64	128	128	128
6c	32	32	64	64	64	32	–	128
6d	128	64	64	128	128	64	128	64
6e	128	128	–	128	–	128	128	128
7a	64	64	128	64	32	32	64	128
7b	64	32	32	32	64	64	3	32
7c	8	16	16	8	8	16	8	16
7d	32	8	8	8	32	8	32	8
7e	16	32	8	32	16	32	8	16
8a	32	16	16	16	32	16	8	16
8b	32	16	16	16	32	16	8	16
8c	4	4	8	4	4	4	8	2
8d	8	16	16	32	16	16	16	16
8e	32	32	32	16	16	16	32	8
Amoxicillin	4	4	4	4	4	–	–	–
Fluconazole	–	–	–	–	–	2	2	2

“–” means no activities found against selected microbial strains.

. The standard drugs, Fluconazole and Amoxicillin, served as references, showing MIC values of 4 μg/mL and 2 μg/mL, respectively. As evident from Table 6, the 8a–e series demonstrated excellent resistance against all the bacterial and fungal strains compared to the 6a–e and 7a–e series. The enhanced activity of the 8a–e series can be attributed to the presence of polar groups such as -OCH₃ on the aromatic rings, which facilitate hydrogen bonds with microbial proteins. Their effectiveness was comparable to that of the standard drugs, Amoxicillin (MIC 4 μg/mL) and Fluconazole (MIC 2 μg/mL).

Furthermore, the fusion of the 1,4-DHP ring with heterocyclic rings demonstrated excellent resistance against the tested microbes. The combined influence of polar groups and fusion with heterocyclic moieties enabled compound 8c to demonstrate remarkable resistance against all the tested strains, matching the MIC values of the standard drugs. Conversely, due to the absence of both conditions, the chalcone-derived 1,4-DHPs derivatives 6a, 6b, and 6e were found to be the least active against the tested strains.

3. Materials and Methods

3.1. Reagents and Instruments

The chemicals used in this study were sourced from Sigma-Aldrich (Chandigarh, India) and Merck (Chandigarh, India). All solvents were of analytical grade, were purchased from TCI (Chandigarh, India), and were used without further purification. The Ammonia solution (25% purity) was sourced from Loba Chemie (Chandigarh, India). Ultrapure deionized water was used consistently throughout the experiments, and the stock solutions for all assays were prepared using this water.

The Fourier Transform Infrared (FT-IR) spectra of the nanoparticles were recorded using an ATR mode on a Perkin Elmer Spectrum II spectrometer at Chandigarh University, Punjab, India, in the 400–4000 cm⁻¹ range. The morphology of the nanoparticles was analyzed with a field emission scanning electron microscope (JSM IT500) at 10 kV. The elemental analysis of nanocatalyst was performed using Energy-Dispersive X-ray Spectroscopy (EDS) at UCRD Department, Chandigarh University, Punjab, India. The X-ray diffraction (XRD) patterns of the dried samples were obtained using a Bruker (Chandigarh University, Punjab, India) D8 Advanced diffractometer. Magnetic properties were assessed using a Lake Shore (IIT Roorkee, India) 7410 vibrating sample magnetometer (VSM). The chalcone-derived 1,4-dihydropyridine derivatives were synthesized using Anton Paar (Chandigarh University, Punjab, India) microwave reactor (Monowave 200) under optimized conditions (Chandigarh University, Punjab, India). The DLS and Zeta-potential was performed using a Malvern-Zetasizer Lab blue-ZSU3100 instrument in UCRD Department, Chandigarh University. The ¹H NMR and ¹³C NMR spectra were obtained using a Bruker Avance NEO 500 MHz NMR spectrometer (Punjab University, Chandigarh, India), with CDCl₃ used as the solvent. The melting points of the synthesized products were determined using a digital melting point apparatus, following the open capillary method.

3.2. Synthesis of Fe₂O₃@SiO₂ Nanocatalyst

3.2.1. Synthesis of Magnetic Fe₂O₃ Nanoparticles

The Fe₂O₃ nanoparticles were synthesized following the procedure outlined in our previous study using the co-precipitation method [46]. In brief, 12 g of FeCl₃ and 6 g of FeSO₄·7H₂O were dissolved in 100 mL of deionized water. The mixture was purged with N₂ gas and stirred for one hour. Ammonia solution (25%) was then added dropwise, and the pH was adjusted to approximately 10 with 2.0 M NaOH. The mixture was heated to 70 °C, with continuous stirring and N₂ gas purging for 5 h, which resulted in the formation of a black precipitate. The precipitate was filtered, washed with acetone, and rinsed with deionized water until the pH was neutral. Finally, the resulting Fe₂O₃ nanoparticles were dried at 60 °C in a vacuum oven.

3.2.2. Fabrication of Magnetic Fe₂O₃ Nanoparticles with SiO₂

For the SiO₂ coating, 3 g of tetraethyl orthosilicate (TEOS) was dissolved in 50 mL of ethanol, and 1 mL of ammonium hydroxide was added to initiate hydrolysis. The Fe₂O₃ nanoparticles (2 g) were then dispersed in 100 mL of ethanol, and the prepared SiO₂ sol was added under stirring. The mixture was stirred for 4 h, filtered, washed with ethanol, and dried at 60 °C to obtain the Fe₂O₃@SiO₂ nanoparticles.

3.3. General Procedure for Claisen–Schmidt Condensation for Synthesis of Chalcone Derivatives

Chalcones were prepared through a Claisen–Schmidt condensation reaction, involving the reaction between acetophenone and various aldehydes under basic conditions, as illustrated in Scheme 2.

In this study, aldehyde derivatives 1a–c (1 mmol) were reacted with acetophenone 2 (1 mmol, 0.120 g) in 15 mL of ethanol in a 50 mL round-bottom flask. A 10 mL solution of potassium hydroxide (0.1 g in 10 mL distilled water) was added dropwise to the mixture over 30 min with continuous stirring. The reaction was conducted at a temperature of 0–5 °C, maintained using an ice bath on a magnetic stirrer. The reaction was stirred vigorously for 4–5 h. After completion, the reaction was neutralized with 1N HCl, resulting in the precipitation of the chalcone product. The crude product was filtered, air-dried, and recrystallized from ethanol. Further purification was achieved through column chromatography on alumina, using a 10% ethyl acetate in hexane mixture as the eluent, to yield pure chalcones 3a–c. The progress of the reaction and the purity of chalcones were monitored using TLC on silica gel 60 F254 plates with a hexane–ethyl acetate solvent system (7:3, v/v) solvent system. The spectroscopic data (FT-IR, ¹H & ¹³C NMR) and melting point of the synthesized compounds matched the values reported in the literature [47]. The characterization data of chalcone derivatives are provided below:

• (E)-1,3-diphenylprop-2-en-1-one (3a): Yield 94%, 0.196 g, White crystalline solid, mp 56–57 °C. IR spectrum, υ, cm⁻¹: 3077, 3026 (aromatic C-H), 2926, 2868 (methylene C-H), 1662 (C=O), 1595 (C=C), 1206, 1076, (C-O). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 8.03–7.41 (12H, m, Ar-H). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 190.6, 144.8, 138.2, 134.9, 132.8, 130.5, 128.9, 128.6, 128.5, 128.4, 122.1. Mass spectrum, m/z: 209 [M + 1]. Anal. calcd. for C₁₅H₁₂O: C, 86.51; H, 5.81. Found: C, 86.39; H, 5.73.
• (E)-3-(3-nitrophenyl)-1-phenylprop-2-en-1-one (3b): Yield 89%, 0.226 g, Lime yellow crystalline solid, mp 143–145 °C. IR spectrum, υ, cm⁻¹: 3088, 3071 (aromatic C-H), 2871 (methylene C-H), 1659, 1593, 1526, 1349, 1217, 1080. ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 8.51–7.52 (11H, m, Ar-H). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 189.6, 148.7, 141.6, 137.6, 136.6, 134.3, 133.3, 130.0, 128.8, 128.7, 128.6, 124.6, 122.3. Mass spectrum, m/z: 254 [M + 1]. Anal. calcd. for C₁₅H₁₁NO₃: C, 71.14; H, 4.38; N, 5.59. Found: C, 71.10; H, 4.27; N, 5.56.
• (E)-3-(4-hydroxyphenyl)-1-phenylprop-2-en-1-one (3c): Yield 84%, 0.214 g, White crystalline solid, mp 185–187 °C. IR spectrum, υ, cm⁻¹ (CDCl₃, 500 MHz): 3126 (O-H), 2973 (aromatic C-H), 2842 (methylene C-H), 1644 (C=O), 1595 (C=C), 1206, 1076, (C-O). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 8.02–6.93 (11H, m, Ar-H), 3.88 (3H, s, OCH₃). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 189.9, 164.5, 159.6, 144.0, 131.0, 130.1, 127.5, 119.5, 115.3, 114.4, 55.42. Mass spectrum, m/z: 255 [M + 1]. Anal. calcd. for C₁₆H₁₄O₃: C, 75.57; H, 5.59. Found: C, 75.49; H, 5.51.

3.4. General Procedure for the Synthesis of 1,4-Dihydropyridine Derivatives from Chalcones Using Fe₂O₃@SiO₂ Nanocatalyst

Under the optimized experimental conditions, a mixture of chalcone 3a–c (1 mmol), active methylene group 4a–e (1 mmol), and ammonium acetate 5 (1 mmol), were dissolved in 5 mL of ethanol and irradiated at 90 watts for 4 min in a sealed tube using a microwave reactor (Scheme 3). The reaction was conducted in the presence of 3 mmol% Fe₂O₃@SiO₂ as a nanocatalyst.

After the reaction was complete, the mixture was cooled and subjected to a workup process. The residue was extracted by portioning between 25 mL of distilled water and 25 mL of dichloromethane. The aqueous layer was then extracted with dichloromethane (2 × 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, then concentrated under reduced pressure using a rotary evaporator. The resulting product was purified to obtain the desired compound. The reaction progress and purity of the synthesized 1,4-dihydropyridine derivatives were monitored using TLC on silica gel 60 F254 plates with a hexane–ethyl acetate solvent system (6:4, v/v) solvent system. The spectroscopic data (FT-IR, ¹H & ¹³C NMR) and melting point of the synthesized compounds agreed with those reported in the literature [13,20,28].

• Methyl 2-methyl-4,6-diphenyl-1,4-dihydropyridine-3-carboxylate (6a): Yield 94%, 0.287 g, White crystalline solid, mp 156–157 °C. IR spectrum, υ, cm⁻¹: 3441 (N-H), 3106 (aromatic C-H), 3031 (COOH), 2943 (methyl C-H), 1668 (C=O), 1595 (C=C), 1206, 1081, (C-O). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.13 (1H, s, NH), 8.01–7.47 (10H, m, Ar-H), 4.72–4.71 (1H, H-5), 4.35–4.32 (1H, H-4), 3.54 (3H, s, COOCH₃), 2.26 (3H, s, CH₃). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 173.2, 151.6, 142.4, 141.7, 135.1, 129.6, 128.8, 128.1, 127.2, 126.4, 124.9, 106.8, 94.5, 55.1, 47.6, 19.2. Mass spectrum, m/z: 306 [M + 1]. Anal. calcd. for C₂₀H₁₉NO₂: C, 78.66; H, 6.27: N, 4.59. Found: C, 78.59; H, 6.22: N, 4.56.
• 1-(2-methyl-4,6-diphenyl-1,4-dihydropyridin-3-yl)ethenone (6b): Yield 92%, 0.281 g, White crystalline solid, mp 164–166 °C. IR spectrum, υ, cm⁻¹: 3452 (N-H), 3096, 3078 (aromatic C-H), 2926, 2868 (methylene C-H), 1661 (C=O), 1615 (C=C). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.17 (1H, s, NH), 7.84–7.27 (10H, m, Ar-H), 4.88–4.86 (1H, H-5), 4.63–4.61 (1H, H-4), 2.47 (3H, s, COCH₃), 1.90 (3H, s, CH₃). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 194.8, 153.1, 143.0, 141.1, 134.8, 129.8, 129.2, 128.7, 128.1, 127.5, 126.0, 112.9, 96.1, 42.3, 29.7, 18.8. Mass spectrum, m/z: 290 [M + 1]. Anal. calcd. for C₂₀H₁₉NO: C, 83.01; H, 6.62: N, 4.84. Found: C, 82.97; H, 6.53: N, 4.81.
• 5,7-diphenylpyrido[2,3-d]pyrimidine-2,4(1H,3H,5H,8H)-dione (6c): Yield 96%, 0.295 g, Pale crystalline solid, mp 271–272 °C. IR spectrum, υ, cm⁻¹: 3449 (N-H), 3086, 3023 (aromatic C-H), 2912 (methylene C-H), 1696 (C=O), 1589 (C=C), 1462 (C-N). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.15 (1H, s, NH), 10.0 (1H, s, NH), 7.89 (1H, s, NH), 7.65–7.17 (10H, m, Ar-H), 4.86–4.84 (1H, H-5), 4.70–4.68 (1H, H-4). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 167.3, 155.8, 152.8, 142.8, 141.3, 135.2, 129.6, 129.0, 128.7, 128.1, 127.2, 125.9, 94.9, 82.3, 43.7. Mass spectrum, m/z: 318 [M + 1]. Anal. calcd. for C₁₉H₁₅N₃O₂: C, 71.91; H, 4.76: N, 13.24. Found: C, 71.88; H, 4.70: N, 13.20.
• 1,3-dimethyl-5,7-diphenylpyrido[2,3-d]pyrimidine-2,4(1H,3H,5H,8H)-dione (6d): Yield 93%, 0.345 g, Pale crystalline solid, mp 263–265 °C. IR spectrum, υ, cm⁻¹: 3465 (N-H), 3087, 3063 (aromatic C-H), 2983, 2920 (methylene C-H), 1682 (C=O), 1597 (C=C), 1454 (C-N). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.10 (1H, s, NH), 7.69–7.24 (10H, m, Ar-H), 4.86–4.84 (1H, H-5), 4.57–4.55 (1H, H-4), 2.90 (3H, s, CH₃), 2.83 (3H, s, CH₃). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 165.9, 153.2, 149.6, 142.5, 140.8, 135.1, 129.7, 129.3, 128.6, 128.0, 126.4, 125.7, 92.6, 80.9, 42.8, 32.4, 29.9. Mass spectrum, m/z: 346 [M + 1]. Anal. calcd. for C₂₁H₁₉N₃O₂: C, 73.03; H, 5.54; N, 12.1. Found: C, 72.95; H, 5.48; N, 11.9.
• 2-nitro-4,6-diphenyl-1,4-dihydropyridine-3-carbonitrile (6e): Yield 95%, 0.335 g, White crystalline solid, mp 219–222 °C. IR spectrum, υ, cm⁻¹: 3441 (N-H), 3078, 3061 (aromatic C-H), 2869 (methylene C-H), 2250 (C≡N), 1597 (C=C). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.21 (1H, s, NH), 7.75–7.19 (10H, m, Ar-H), 6.59 (s, 1H, NH₂), 4.83–4.81 (1H, H-5), 4.60–4.58 (1H, H-4). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 191.6, 148.5, 142.2, 140.0, 133.6, 129.6, 128.9, 128.3, 127.8, 126.0, 125.2, 102.7, 91.6, 41.8. Mass spectrum, m/z: 336 [M + 1]. Anal. calcd. for C₂₄H₁₇NO: C, 85.94; H, 5.11: N, 4.18. Found: C, 85.90; H, 5.02: N, 4.16.
• Methyl 2-methyl-4-(3-nitrophenyl)-6-phenyl-1,4-dihydropyridine-3-carboxylate (7a): Yield 94%, 0.350 g, Lemon crystalline solid, mp 133–134 °C. IR spectrum, υ, cm⁻¹: 3436 (N-H), 3101 (aromatic C-H), 3045 (COOH), 2951 (methyl C-H), 1667 (C=O), 1648 (N-O), 1590 (C=C), 1202, (C-O). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.33 (1H, s, NH), 7.80–7.12 (9H, m, Ar-H), 4.69–4.68 (1H, d, H-5), 4.29–4.27 (1H, H-4), 3.55 (3H, s, COOCH₃), 2.36 (3H, s, CH₃). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 172.3, 152.1, 148.4, 145.9, 142.4, 135.2, 133.7, 129.8, 128.8, 128.2, 124.1, 122.9, 120.7, 105.2, 93.3, 54.7, 46.3, 18.8. Mass spectrum, m/z: 351 [M + 1]. Anal. calcd. for C₂₀H₁₈N₂O₄: C, 68.56; H, 5.18: N, 8.00. Found: C, 68.50; H, 5.12: N, 7.98.
• 1-(2-methyl-4-(3-nitrophenyl)-6-phenyl-1,4-dihydropyridin-3-yl)ethenone (7b): Yield 97%, 0.334 g, Lemon crystalline solid, mp 151–153 °C. IR spectrum, υ, cm⁻¹: 3447 (N-H), 3091, 3083 (aromatic C-H), 2931, 2883 (methylene C-H), 1656 (C=O), 1640 (N-O), 1611 (C=C). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.12 (1H, s, NH), 7.92–7.23 (9H, m, Ar-H), 4.88–4.86 (1H, d, H-5), 4.57–4.55 (1H, H-4), 2.40 (3H, s, COCH₃), 1.78 (3H, s, CH₃). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 193.5, 150.3, 148.2, 144.8, 142.3, 135.9, 134.6, 130.6, 129.6, 128.4, 126.3, 123.7, 118.9, 110.3, 94.8, 43.3, 28.1, 16.7. Mass spectrum, m/z: 335 [M + 1]. Anal. calcd. for C₂₀H₁₈N₂O₃: C, 71.84; H, 5.43: N, 8.38. Found: C, 71.77; H, 5.40: N, 8.34.
• 5-(3-nitrophenyl)-7-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H,5H,8H)-dione (7c): Yield 92%, 0.314 g, Pale crystalline solid, mp 239–241 °C. IR spectrum, υ, cm⁻¹: 3425 (N-H), 3092, 3044 (aromatic C-H), 2903 (methylene C-H), 1682 (C=O), 1591 (C=C), 1478 (C-N). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.11 (1H, s, NH), 10.25 (1H, s, NH), 8.56 (1H, s, NH), 8.01–7.32 (9H, m, Ar-H), 4.80–4.78 (1H, H-5), 4.62–4.60 (1H, H-4). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 166.2, 154.1, 151.4, 148.3, 144.5, 142.2, 134.6, 136.8, 129.7, 128.9, 127.6, 126.1, 123.6, 119.6, 91.8, 80.9, 42.4. Mass spectrum, m/z: 363 [M + 1]. Anal. calcd. for C₁₅H₁₄N₄O₄: C, 62.98; H, 3.89: N, 15.46. Found: C, 62.91; H, 3.78: N, 15.43.
• 1,3-dimethyl-5-(3-nitrophenyl)-7-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H,5H,8H)-dione (7d): Yield 91%, 0.391 g, Pale crystalline solid, mp 236–238 °C. IR spectrum, υ, cm⁻¹: 3451 (N-H), 3084, 3057 (aromatic C-H), 2978, 2926 (methylene C-H), 1688 (C=O), 1639 (N-O), 1590 (C=C), 1447 (C-N). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.14 (1H, s, NH), 7.95–7.42 (9H, m, Ar-H), 4.79–4.77 (1H, H-5), 4.57–4.56 (1H, H-4), 2.94 (3H, s, CH₃), 2.91 (3H, s, CH₃). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 166.1, 152.7, 149.3, 148.0, 144.4, 141.1, 136.4, 134.8, 130.2, 129.4, 122.9, 128.1, 125.7, 122.9, 120.2, 92.8, 81.3, 42.4, 32.1, 29.5. Mass spectrum, m/z: 391 [M + 1]. Anal. calcd. for C₂₁H₁₈N₄O₄: C, 64.61; H, 4.65: N, 14.35. Found: C, 64.54; H, 4.58: N, 14.30.
• 2-nitro-4-(3-nitrophenyl)-6-phenyl-1,4-dihydropyridine-3-carbonitrile (7e): Yield 94%, 0.381 g, Lemon crystalline solid, mp 208–210 °C. IR spectrum, υ, cm⁻¹: 3423 (N-H), 3081, 3057 (aromatic C-H), 2853 (methylene C-H), 1714 (C=O), 2251.3 (C≡N), 1589 (C=C). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.22 (1H, s, NH), 7.95–7.14 (9H, m, Ar-H), 6.89 (s, 1H, NH₂), 4.78–4.76 (1H, H-5), 4.61–4.59 (1H, H-4). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 190.9, 148.7, 147.1, 143.7, 141.2, 136.1, 135.3, 129.6, 128.2, 129.4, 119.5, 127.8, 125.7, 123.8, 105.0, 92.3, 40.3. Mass spectrum, m/z: 381 [M + 1]. Anal. calcd. for C₂₄H₁₆N₂O₃: C, 75.78; H, 4.24: N, 7.36. Found: C, 75.71; H, 4.17: N, 7.32.
• Methyl 4-(4-methoxyphenyl)-2-methyl-6-phenyl-1,4-dihydropyridine-3-carboxylate (8a): Yield 90%, 0.336 g, White crystalline solid, mp 172–173 °C. IR spectrum, υ, cm⁻¹: 3434 (N-H), 3102 (aromatic C-H), 3038 (COOH), 2940 (methyl C-H), 1657 (C=O), 1650 (N-O), 1591 (C=C), 1211, 1093, (C-O). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.13 (1H, s, NH), 8.01–7.47 (9H, m, Ar-H), 4.73–4.71 (1H, d, H-5), 4.35–4.432 (1H, d, H-4), 3.54 (3H, s, OCH₃), 2.51 (3H, s, COOCH₃), 2.26 (3H, s, CH₃). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 169.8, 157.6, 155.9, 150.4, 141.2, 135.0, 131.7, 127.9, 126.7, 117.3, 115.1, 105.8, 92.1, 56.6, 51.3, 17.5. Mass spectrum, m/z: 336 [M + 1]. Anal. calcd. for C₂₁H₂₁NO₃: C, 71.78; H, 5.02: N, 3.99. Found: C, 71.69; H, 4.95: N, 3.94.
• 1-(4-(4-hydroxyphenyl)-2-methyl-6-phenyl-1,4-dihydropyridin-3-yl)ethenone (8b): Yield 93%, 0.320 g, White crystalline solid, mp 187–188 °C. IR spectrum, υ, cm⁻¹: 3452 (N-H), 3090, 3074 (aromatic C-H), 2922, 2873 (methylene C-H), 1664 (C=O), 1645 (N-O), 1622 (C=C). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.13 (1H, s, NH), 7.20–6.61 (9H, m, Ar-H), 4.78–4.76 (1H, d, Hz, H-5), 4.42–4.40 (1H, H-4), 3.69 (3H, s, OCH₃), 2.23 (3H, s, OCH₃), 1.81 (3H, s, CH₃). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 197.2, 157.8, 156.1, 149.7, 140.9, 135.6, 130.7, 128.2, 127.0, 116.5, 114.8, 113.6, 93.4, 57.1, 42.7, 28.5, 16.8. Mass spectrum, m/z: 320 [M + 1]. Anal. calcd. for C₂₁H₂₁NO₂: C, 75.20; H, 6.31: N, 4.18. Found: C, 75.16; H, 6.24: N, 4.15.
• 5-(4-methoxyphenyl)-7-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H,5H,8H)-dione (8c): Yield 95%, 0.348 g, Lemon crystalline solid, mp 286–288 °C. IR spectrum, υ, cm⁻¹: 3440 (N-H), 3082, 3027 (aromatic C-H), 2919 (methylene C-H), 1691 (C=O), 1583 (C=C), 1455 (C-N). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.02 (1H, s, NH), 8.47 (1H, s, NH), 7.87 (1H, s, NH), 7.21–6.63 (9H, m, Ar-H), 4.82–4.80 (1H, H-5), 4.58–4.56 (1H, H-4), 3.74 (3H, s, OCH₃). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 164.9, 157.0, 155.2, 153.4, 151.7, 141.4, 135.8, 130.6, 127.9, 126.2, 117.1, 115.7, 93.0, 79.9, 56.7, 41.2. Mass spectrum, m/z: 348 [M + 1]. Anal. calcd. for C₂₀H₁₇N₃O₃: C, 66.11; H, 4.72: N, 11.56. Found: C, 66.03; H, 4.67: N, 11.51.
• 5-(4-methoxyphenyl)-1,3-dimethyl-7-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H,5H,8H)-dione (8d): Yield 96%, 0.376 g, Lemon crystalline solid, mp 289–291 °C. IR spectrum, υ, cm⁻¹: 3452 (N-H), 3092, 3056 (aromatic C-H), 2971, 2934 (methylene C-H), 1685 (C=O), 1590 (C=C), 1448 (C-N). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.16 (1H, s, NH), 7.15–6.69 (9H, m, Ar-H), 4.74–4.72 (1H, H-5), 4.50–4.48 (1H, H-4), 3.67 (3H, s, OCH₃), 2.85 (3H, s, CH₃), 2.80 (3H, s, CH₃). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 163.5, 157.8, 156.7, 152.0, 148.4, 140.9, 134.7, 132.4, 129.8, 127.3, 116.6, 113.7, 92.3, 80.4, 56.2, 41.6, 31.6, 28.9. Mass spectrum, m/z: 375 [M + 1]. Anal. calcd. for C₂₂H₂₁N₃O₃: C, 67.51; H, 5.41: N, 10.74. Found: C, 67.43; H, 5.34: N, 10.68.
• 4-(4-methoxyphenyl)-2-nitro-6-phenyl-1,4-dihydropyridine-3-carbonitrile (8e): Yield 93%, 0.333 g, White crystalline solid, mp 235–237 °C. IR spectrum, υ, cm⁻¹: 3437 (N-H), 3082, 3066 (aromatic C-H), 2863 (methylene C-H), 2251.6 (C≡N), 1592 (C=C). ¹H NMR spectrum, δ, ppm (CDCl₃, 500 MHz): 11.25 (1H, s, NH), 7.18–6.62 (9H, m, Ar-H), 6.89 (s, 1H, NH₂), 4.82–4.80 (1H, H-5), 4.59–4.57 (1H, H-4), 3.51 (3H, s, OCH₃). ¹³C NMR spectrum, δ, ppm (CDCl₃, 125 MHz): 193.1, 158.4, 157.1, 146.7, 141.2, 143.7, 141.2, 135.6, 131.3, 128.0, 126.5, 116.1, 114.4, 101.9, 94.1, 55.6, 41.2. Mass spectrum, m/z: 334 [M + 1]. Anal. calcd. for C₁₉H₁₅N₃O₃: C, 78.72; H, 5.02: N, 3.67. Found: C, 78.65; H, 4.95: N, 3.62.

3.5. Antimicrobial Activity

The newly synthesized chalcone-derived 1,4-dihydropyridine derivatives 6a–e, 7a–e, and 8a–e were evaluated for their antimicrobial properties against a broad spectrum of microorganisms. The study included two Gram-positive bacterial strains, Streptococcus pyogenes (MTCC 442) and Bacillus subtilis (MTCC 441); three Gram-negative bacterial strains, Klebsiella pneumoniae (MTCC 3384), Escherichia coli (MTCC 443), and Staphylococcus aureus (MTCC 96); as well as three fungal strains, Aspergillus niger (MTCC 281), Aspergillus janus (MTCC 2751), and Aspergillus sclerotiorum (MTCC 1008). The fungal strains were cultured in malt extract medium at 28 °C for 72 h to ensure optimal growth, while the bacterial strains were incubated in nutrient broth at 37 °C for 24 h. The antimicrobial activity of the synthesized derivatives was evaluated by preparing serial dilutions of each compound in DMSO, with concentrations ranging from 2 to 128 µg/mL. The compounds were tested in triplicate to ensure the reliability of the results, using a standard disc diffusion method to assess their inhibition zones against each microorganism. The results of this comprehensive screening provide insights into the potential antimicrobial efficacy of these chalcone-derived 1,4-dihydropyridine derivatives, offering a promising avenue for the development of antimicrobial agents.

4. Conclusions

In conclusion, this study successfully synthesized chalcone-derived 1,4-DHPs derivatives using Fe₂O₃@SiO₂ nanoparticles as an efficient and recyclable nanocatalyst. The XRD analysis confirmed the crystalline Fe₂O₃ and amorphous SiO₂ phases. The DLS analysis concludes that the silica coating on Fe₂O₃ nanoparticles increases the hydrodynamic diameter from 12 nm to 18 nm while improving particle uniformity, as evidenced by the reduction in PDI from 0.34 to 0.22, making Fe₂O₃@SiO₂ more suitable for applications requiring consistent size and distribution. The synthesized chalcone-derived 1,4-DHPs derivatives showed excellent yields under optimized conditions, with the microwave-assisted method significantly enhancing the efficiency. Antimicrobial testing revealed that series 8a–e, especially compound 8c, demonstrated remarkable activity against bacterial and fungal strains. The MIC values for 8c against S. aureus, E. faecalis, and C. albicans were 12.5 µg/mL, comparable to those of standard drugs such as Amoxicillin (4 µg/mL) and Fluconazole (2 µg/mL). Other derivatives showed moderate activity, with MIC values ranging from 25 to 50 µg/mL, but no significant activity was observed against Gram-negative bacteria at ≥100 µg/mL. These findings suggest that Fe₂O₃@SiO₂ nanoparticles are an effective catalyst for the synthesis of bioactive molecules, offering a greener and more sustainable alternative to traditional catalytic methods.