A very efficient Pd-built catalytic system for the Suzuki Miyaura SM coupling of nicotinaldehydes were developed under gentle reaction conditions. Analytical techniques included FTIR, Uv-Visible, 1H NMR, and 13C NMR, whereas computational analysis used during the investigation involved density functional (DFT), Molecular docking PASS, ADMET and drug likeness. In the current investigation, new nicotinaldehyde compounds i;e 2-(2,3-dimethylphenyl) nicotinaldehyde DMPN, 2-(3-bromophenyl) nicotinaldehyde BrPN, 2-(4-(tert-butyl)-[1, 1-biphenyl]-4-yl) nicotinaldehyde tBuBPN were synthesized. In computational analysis HOMO-LUMO band gaps (Egap) were obtained in the range of 0.14947–0.15888 eV. By using spectroscopic analysis such as FTIR, Uv-Visible, 1H NMR, and 13C NMR, the structures of new synthesized composites were verified. Molecular docking of compounds revealed stable strong interaction with 1JIJ and 2XET. All drug molecules followed drug likeness rules and PASS analysis revealed significant antimicrobial potential high confidence interval (0.329–0.751). The antimicrobial evaluation of tested molecules revealed significant inhibition of oral pathogens including Pseudomonas aeruginosa, Bacillus chungangensis1, Bacillus paramycoides, Bacillus chungangensis2 and Paenibacillus dendritiformis (MIC 1.56–49.2µg/mL). Further significant antibiofilm were recorded in case of DMPN (1.56–6.24 µg/mL) and M2 (MIC 1.56–6.24 µg/mL), whereas all three compounds presented moderate (54–57%) antiquorum sensing activity. It was therefore concluded that compounds DMPN and BrPN possessed strong activities against oral pathogens.
Research Article
Novel Nicotintaldehyde Derivatives via Pd (0) Catalyzed Suzuki Coupling Approach; Characterization, DFT and Molecular Docking and evaluation of anti-antibiofilm, antiquorum sensing activities against Oral pathogens
https://doi.org/10.21203/rs.3.rs-4775300/v1
This work is licensed under a CC BY 4.0 License
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Suzuki coupling
computation analysis
Oral pathogens
Biofilms
heterocyclic compounds
Palladium's exceptional ability to create C-C bonds between appropriately functionalized substrates has allowed synthetic organic chemists to perform transformations that were either previously unachievable or only conceivable using multi-step procedures [1–3]. These cross-coupling approaches have completely changed the way that people think about synthetic organic chemistry because of how widely they are used in organic synthesis and material science, as well as how much they have contributed to the pharmaceutical, agrochemical, and fine chemical industries [4, 5].
Without a doubt, one of the most often used methods for forming a C-C is the Suzuki coupling (SMC), which includes combining the organic molecules in base, a palladium catalyst, and both, is a type of chemical bond [6–8]. This cross-coupling process has numerous distinct benefits over previous cross-coupling reactions mediated by palladium. A few of these benefits include mild reaction conditions, simple access to organo-boron reagents that are inert to oxygen, water, and related solvents, tolerance to a variety of functional groups, and less toxic by-products and starting materials [9–11]. These properties have allowed researchers to use it for a variety of applications, including the synthesis of natural products [12, 13], the creation of polymeric materials [14–16], and organic photovoltaics [17–19].
Since nitrogen-containing heterocycles are frequently found to be bioactive molecules in nature, they are incredibly interesting for investigation. Since N-heterocycles are frequently used, it is necessary to figure out how to make them more productive to produce, as well as to research how modifying them might affect them and how effective they are biologically, naturally, and technologically. Medical chemists have accelerated the synthesis of complex heterocyclic structures using microwave-assisted organic synthesis (MAOS) [20–25].
The most common and important heterocyclic compounds are pyridine derivatives [26], which have many uses in a range of fields, including nonlinear optics [27–29], organic photovoltaics [30, 31], medicine, and natural products [32]. Pyridine derivatives have a range of biological actions, including those that are antifungal, antiglycating, antiseptic, ulcerogenic, antioxidant, anticonvulsant, palliative, antiparkinsonian, anti-inflammatory, antiviral, and anticancer action [33, 34]. Additionally, these derivatives have a potent affinity for a wide range of ions and neutral compounds. Based on the characteristics of electrophilic and nucleophilic substituents, pyridines serve as the forefathers for electron and hole carrying components in organic solar cells (OSCs), small molecule OSCs, dye-sensitized solar cells, and NLO materials [35].
Oral Microbiome is quiet diverse and is comprised of above 30 diverse bacterial general [36]. Both regular and transient bacteria have been reported in oral cavity including bacilli, cocci, aerobes, anaerobes, mycoplasma and treponemes [37–38]. In addition to their normal roles, several of them (around 400 species) are responsible to produce biofilms, that are main reason for development of severe complications including gingivitis, periodontitis, mouth ulcers and finally systemeic complications [39–40].
Bacterial biofilms are major source of development of resistance to antimicrobial agents and are very difficult to treat due to their heterogeneous structure [41]. These not only limit the entry of antimicrobial agents, but also cause certain genetic mutations that make drug inactive [42–43]. Due to emergence of global resistance against oral biofilms, there exist a great need to look for new drug leads. This project aimed to synthesize novel biphenyl motifs using Suzuki Miayaura cross coupling reaction, their charcaterization using NMR, FTIR, and UV-Visible analysis and to investigate the intramolecular chemistry through DFT and TD-DFT investigations.
1 H NMR & 13CNMR Spectral Analysis
In the 1HNMR of DMPN, a singlet resonated at δ = 10.087 ppm is due to the aldehydic proton, the doublet appeared at δ = 9.797 is due to the CH proton C6 of the pyridinyl ring. Similarly, the doublets resonated at δ = 8.924, 7.840 and 7.711 ppm are due to the CH protons of C4, C10, C12 respectively and the multiplets peaks resonated at δ = 7.676, 7.593 ppm are due to the C5 and C11. The intensified singlets appeared at δ = 2.307 and 2.071 ppm are due to the two CH3 groups at C8 and C9. Similarly, for 13C NMR of DMPN the peak resonated at δ = 191.76 ppm is assigned to the carbonylic carbon (C = O) attached to the quarternary carbon atom C3 resonating at 163.07 ppm, whereas the peaks appeared at δ = 20.45 and 16.80 are due to the two methyl (CH3) groups attached to the quraternary carbons C8, C9 at δ = 137.56 ppm. Similarly, the peaks at δ = 135.47, 130.70, 129.97, 128.49, 125.60 and 123.60 are owing to six methine carbons (CH) C4, C5, C6, C10, C11 and C12 however, the analogous peaks δ = 154.04 ppm is due to the two quarternary carbons C2 and C7 respectively.
In the 1HNMR of BrPN, a singlet resonated at δ = 10.086 ppm is due to the aldehydic proton, the doublet appeared at δ = 8.923 ppm is due to the CH proton C6 of the pyridinyl ring. Similarly, the doublets resonated at δ = 8.364, 7.701, 7.530 and 7.489 ppm are due to the four CH protons of C4, C8, C10, C12 respectively and the multiplet peak resonated at δ = 7.838 ppm is due to the two CH protons of C5 and C9. Similarly, for 13CNMR of BrPN the peak resonated at δ = 191.65 ppm is assigned to the carbonylic carbon (C = O) attached to the quarternary carbon atom C3 resonating at 153.96 ppm. Similarly, the peaks at δ = 153.96, 136.60, 132.98, 130.92, 130.06, 123.95 and 122.21 are owing to seven methine carbons (CH) C4, C5, C6, C8, C9, C10 and C12 however, the analogous peaks δ = 159.67 ppm is due to the two quarternary carbons C2 and C7 respectively.
In the 1H NMR of tBuBPN, a singlet resonated at δ = 10.165 ppm is due to the aldehydic proton, the doublet appeared at δ = 9.148 ppm is due to the CH proton C6 of the pyridinyl ring. Similarly, the doublets resonated at δ = 8.282, 8.007, 7.970, 7.718, 7.665 and 7.574 ppm are due to the nine CH protons of C4, C8, C12, C9, C11, C14, C18, C15 and C17 respectively and the multiplet peak resonated at δ = 8.176 ppm is due to the one CH proton of C5 of the pyridinyl moiety. The intensified singlets appeared at δ = 1.40 and 1.352 ppm is due to the tertiary butyl group at C19. Similarly, for 13CNMR of tBuBPN the peak resonated at δ = 192.47 ppm is assigned to the carbonylic carbon (C = O) attached to the quarternary carbon atom C3 resonating at 159.68 ppm whereas the peaks appeared at δ = 31.52 is due to the three tertiary butyl (CH3) groups attached to the quaternary carbon C19 at δ = 34.86 ppm. Similarly, the peaks at δ = 137.05, 134.47, 132.45, 130.62, 129.78, 124.67 and 121.02 are owing to eleven methine carbons (CH) C4, C5, C6, C8, C9, C11, C12, C14, C15, C17 and C18 however, the analogous peaks δ = 159.68, 152.91, 152.16 and 137.86 ppm is due to the five quarternary carbons C2, C7, C10, C13 and C16 respectively.
FTIR Spectral Analysis
C-H Aromatic Stretching
The C-H aromatic frequencies for DMPN and BrPN were found at 2924.21 and 2958.30 cm− 1, however for tBuBPN the C-H aromatic stretching occur at 2958.38.
C-H Aldehydic Stretching
The C-H aledehydic stretching frequencies for DMPN and BrPN were found at 2858.33 and 2858.57 cm− 1, likewise for tBuBPN the C-H aledehydic stretching occur at 2859.12 cm− 1.
C = O Stretching
The C = O carbonyl stretching frequencies for DMPN and BrPN were found at 1696.98 and 1723.26 cm− 1, likewise for tBuBPN the C = O carbonyl stretching vibration occur at 1725.42 cm− 1.
C = C Stretching
The C = C aromatic stretching vibrations for DMPN and BrPN were found at 1534.92 and 1556.34 cm− 1, similarly for tBuBPN the C = C aromatic stretching vibration occur at 1565.00 cm− 1.
C = N Stretching
The C = N aromatic stretching vibrations for DMPN and BrPN were found at 1579.31 and 1534.92 cm− 1, similarly for tBuBPN the C = C aromatic stretching vibration occur at 1591.51 cm− 1.
CH 3 Bending
The CH3 bending vibrations for DMPN and tBuBPN were found at 1446.14 and 1466.47 cm− 1.
Computational Analysis
Geometry optimization
The molecular structures of compounds BrPN, DMPN and tBuPN were modeled as three dimensional in Gaussian 09 package and optimized [44] each geometry at B3LYP/6311 G, (d,p) level of theory and are given in Figure-2. Each optimized geometry was further used for probe of electronic properties such as frontier molecular orbitals, molecular electrostatic potential map, UV and frequency analysis.
Frontier Molecular Orbitals (FMOs)
FMOs are highest occupied molecular orbitals (HOMO) and lowest unoccupied molecular orbitals (LUMO) and consider as core participant in molecular interaction[38]. The energy of HOMO and LUMO refers as ionization potential and electron affinity, respectively, because HOMO has tendency to donate electrons while LUMO has tendency to accept electrons. Different methods are used in computational chemistry to explain the FMOs. Here we applied B3LYP/6311 G, (d,p) level of theory to investigate the FMOs of synthesized compounds and their respective energy values which are tabulated in Table-1. The plots of FMOs are shown in Figure-3. FMOs analysis showed that electrons density is intensively present on benzene rings, Br and N atom of pyridine rings whilst least electrons density is found on carbonyl group and pyridine rings of investigated compounds.
Global Reactivity Parameters (GRP)
The energy values of HOMO and LUMO are most productive to describe the reactivity and stability of a compound[45–46]. The larger difference of HOMO- LUMO (ΔE) and greater values of chemical potential (µ) and global electrophilicity (ω) high will be it dynamic stability and rare will be its reactivity and vice versa. Among the investigated compounds, the BrPN HOMO-LUMO energy difference is ΔE = 0.15888 which is slightly higher than DMPN and tButPBN due to attachment of large size of Br atom. Moreover, bioactivity of organic compound can explain based on µ, is compound low negative value, higher will be bioactivity. The tButPBN has low negative value of µ, therefore, it will more active towards bioactivity. Furthermore, the organic compound has higher value of softness (S), smaller value will be of hardness (ɳ) and vice versa. The compound has high value of S higher will be it reactivity and lower will be stability while compound has higher value of ɳ, greater will be it stability and lower be it reactivity. Among synthesized compounds, the tButPBN has large value of S and small value of ɳ predicts that it has higher reactivity and lower stability. In contrast, the BrPBN has small value of S and large of ɳ envisage that it has less reactivity and greater stability.
Molecular Electrostatic Potential map (MEP)
The reactivity behavior of a compound can be explained based on MEP which is one of the fascinating feature of quantum chemical investigation. The MEP plots of synthesized compounds are present in Figure-4. The MEP ostensibly predicts the electrophilic and nucleophilic sites in investigated compounds. When MEP maps of newly prepared compounds computed range of colors regions appeared such blue, yellowish, green and blue over each compound. The green region is neutral, the yellowish and red colors (regions) are electron rich sites which are preferable for an electrophile attacking while the blue color is electron deficient and preferable for nucleophile attacking[47].
Uv-Visible Analysis:
The experimentally maximum absorption for DMPN and BrPN appeared at λmax = 302nm and λmax = 320 nm, however for tBuBPN the maximum absorption occurs at λmax = 335nm respectively. While computed maximum absorption [48] for BrPN, DMPN and tButBPN noted at 322, 299 and 327 nm respectively, in ethyl acetate (solvent) using IEFPCM model. Computed analysis showing good agreement with experimentally obtained results. The computed UV-spectrums are given in SI.
Frequency analysis:
The frequency simulations were performed at same method as used for optimization. The frequency of each functional group was assigned using correction factor 0.94, 0.98 and 0.97 for BrPN, DMPN and tButBPN, respectively.
C-H Aromatic Streching:
The computed C-H aromatic frequencies for BrPN and DMPN were observed at 2955.97 and 2969.49 cm− 1, while stretching frequency of aromatic C-H for tBuBPN n at 2939.31 cm− 1.
C-H Aldehydic Streching:
The computed C-H aledehydic stretching frequencies for BrPN and DMPN were noted at 2867.67 and 2796. 01 cm− 1, likewise stretching frequency for C-H aledehydic of tBuBPN found at 2868.83 cm− 1.
C = O Streching:
The computed C = O carbonyl stretching vibration for BrPN and DMPN were found at 1653.21 and 1756.18 cm− 1, respective, likewise for tBuBPN the C = O carbonyl stretching frequency occur at 1711.12 cm− 1.
C = C Streching:
The computed C = C bond aromatic stretching vibrations for BrPN and DMPN were appeared at 1526.59 and 1556.23 cm− 1, respectively, similarly for tBuBPN the C = C aromatic stretching frequency occur at 1546.83 cm− 1.
C = N Streching:
The computed C = N aromatic stretching vibrations for BrPN and DMPN were noted at 1534.51 and 1591.67 cm− 1, while for tBuBPN the C = C aromatic stretching vibration occur at 1571.93 cm− 1.
CH 3 Bending:
The computed bending vibrations of CH3 for DMPN and tBuBPN were found at 1449.76 and 1465.01 cm− 1, respectively. The computed frequency spectrums of synthesized compounds are given in SI.
Computed and experimental 1H NMR correlation
The computed chemical shifts (δ) were simulated on Gage Invariance Atomic Orbital (GIAO) method both in gas phase and solvent phase using IEFPCM model [45]. The correlation of computed chemical shifts and experimental chemical shifts are given in Figure-5 and their 1H NMR spectrums are given SI.
The computed chemical shift of aldehydic proton appeared in range from 10.2 ppm to 11.69 ppm for investigated compounds. The C-H of pyridine rings, computed chemical shifts are noted in region from 8.9 ppm to 9.6 ppm. Similarly, aromatic 1H NMR are observed from 7.1 ppm to 8.8 ppm region while CH3 chemical shifts are recoded from 1.1 ppm to 2.4 ppm region. The chemical shifts values in both gas and solvent phases were compared with experimental chemical shifts and their R2 values is equal 1 which showed good agreement of experimental and computed chemical shifts.
ADMET Profiling and Drug likeness and Toxicity assessment
The synthesized compounds M1-M3 were evaluated for insilico analysis and it was evident that all molecules followed drug likeness rules and no violations were recorded (Table 2; Fig. 6). Further, all the pyridine base synthetic compounds were subjected to the computational analysis to predict the drug likeness, bioavailability, lipophilicity, drug likeness score and all the pharmacokinetics parameters (Fig. 6; Table 3). It was observed that all synthetic analogues followed the drug likeness rules and their predicted values of lipophilicity, size, polarity and flexibility regarding bioavailability were within permissible range, thereby it was concluded that compounds possessed good bioavailability [49]. Finally the synthetic analogues were Checked on PASS online tool for possible antimicrobial potential and predicted values Pi > 10% (Table 4) that were in agreement with significant antimicrobial potential for analogues against diverse microrganisms [50].
| Complex | HOMO (eV) | LUMO (eV) | ΔΕ (eV) | ɳ (eV) | µ (eV) | ω (eV) | S (softness) Ev | χ (Mulliken electronegativity) eV |
|---|---|---|---|---|---|---|---|---|
| BrPN | -0.25344 | -0.09456 | 0.15888 | 0.07944 | -0.174 | 0.190559 | 0.758125 | -4.95428 |
| DMPN | -0.2335 | -0.08041 | 0.15309 | 0.076545 | -0.15696 | 0.160918 | 1.512518 | -5.98208 |
| tButPBN | -0.22937 | -0.0799 | 0.14947 | 0.074735 | -0.15464 | 0.159978 | 1.51844 | -5.69471 |
| Compound | Molecular Wt < 500Da | Log p < 5 | H-Bond donors (< 5) | H-Bond acceptor < 10 | No of violations |
|---|---|---|---|---|---|
| DMPN | 254.12 | 4.13 | 2 | 0 | 0 |
| BrPN | 217.70 | 4.26 | 1 | 0 | 0 |
| tBuBPN | 315.41 | 5.88 | 2 | 0 | 0 |
| Parent drug DMPN, BrPN | 141.56 | 1.46 | 2 | 0 | 0 |
| Parent Drug tBuBPN | 186.28 | 1.42 | 3 | 1 | 0 |
| Properties | Compounds | ||
|---|---|---|---|
| DMPN | BrPN | tBuBPN | |
| TPSA (A°) | 22.12 Ų | 12.89 Ų | 29.96 Ų |
| Consensus Log Po/w | 3.57 | 3.71 | 4.73 |
| Absorption | |||
| Water solubility (logmol/L) | -4.056 | -4.016 | -5.054 |
| CaCo2 permeability (log Papp in 10 − 6 cm/s) | 1.284 | 1.557 | 1.216 |
| Intestinal absorption (human) (% absorbed) | 94.548 | 94.48 | 96.118 |
| Skin permeability (log Kp) | -2.128 | -1.849 | -2.73 |
| P-Glycoprotein substrate | No | Yes | No |
| P-Glycoprotein I inhibitor | No | No | No |
| P-Glycoprotein II inhibitor | No | No | Yes |
| Distribution | |||
| VDss (human, log L/kg) | -0.002 | 0.144 | 0.082 |
| Fraction unbound (human) (Fu) | 0.221 | 0.239 | 0.191 |
| BBB permeability(logBB) | 0.183 | 0.368 | 0.38 |
| CNS permeability (log PS) | -1.636 | -1.589 | -1.07 |
| Metabolism | |||
| CYP2D6 substrate | No | No | No |
| CYP3A4 substrate | No | No | Yes |
| CYP1A2 inhibitor | Yes | Yes | Yes |
| CYP2C19 inhibitor | Yes | Yes | Yes |
| CYP2C9 inhibitor | No | No | Yes |
| CYP2D6 inhibitor | No | No | No |
| CYP3A4 inhibitor | No | No | No |
| Excretion | |||
| Total clearance (logml/min/kg) | 0.214 | 0.039 | 0.262 |
| Renal OCT2 substrate | No | No | No |
| Toxicity | |||
| AMES toxicity | No | No | No |
| hERG I inhibitor | No | No | No |
| hERG II inhibitor | No | No | Yes |
| Hepatotoxicity | No | No | Yes |
| Skin sensitization | No | No | No |
Table 4: PASS analysis of tested compounds.
Molecular Docking analysis
The interaction analysis of molecules was performed by using Molecular docking against transcription regulator 1JIJ [51] and 2XCT [52] respectively related to Biofilm formation of Bacillus sp. In case of 1JIJ the synthetic analogous tButPBN was able to present significant interaction with target gene. The tButPBN showed a high free binding energy (-7.8 ΔG (kJ mol‒1) at pose 1 and interacted with Tyr170, Lys84, Tyr36 amino acids through H bonding (Table xxx, figure xxx). Here the hydrophobic interactions included Gln196, Asp80, Gln174, Leu70, Asp177, Asp40, Gln190, Gly38 and Asp195 respectively that interacted through vandervaal’s, halogen π-alkyl interactions (Fig. 7; Table 5).
| Compound | Binding free energy ΔG (kJ mol‒1) | Pose No | No of H bonds | Amino acid Interaction residues | Hydrophobic interactions with amino acids |
|---|---|---|---|---|---|
| 1JIJ | |||||
| DMPN | -6.9 | 1 | 0 | 0 | Lys305, Glu302, Phe273, Phe306 |
| BrPN | -6.5 | 1 | 0 | 0 | Ile131, Leu128, Phe136, Leu133, Thr169, Leu173 |
| tBuBPN | -7.8 | 1 | 2 | Tyr170, Lys84, Tyr36 | Gln196, Asp80, Gln174, Leu70, Asp177, Asp40, Gln190, Gly38Asp195 |
| 2XET | |||||
| DMPN | -6.2 | 1 | 0 | 0 | Ile797, Gly724, Gly723, Leu791, Lys769, Glu793, Tyr801, Thr795, Lys794, Pro792 |
| BrPN | -5.1 | 4 | 1 | Thr745 | Ile743, Gln749, Ser750, Leu774, Lys776 |
| tBuBPN | -6.6 | 1 | 1 | Arg725 | Gly724, Gly723, Pro729, Ile797, Lys794,Glu793, Lys769, Leu791,Tyr801 |
In case of 2XCT both BrPN and tButPBN showed H-bonding interactions. The synthetic analogous M2 presented significant interaction with Thr745 with a high free binding energy (-5.1 ΔG (kJ mol‒1) at pose 1 and hydrophobic interaction included Ile743, Gln749, Ser750, Leu774 and Lys776 amino acids (Fig. 8; Table 5). The M3 on the other hand showed significant H-bonding interaction with Arg725 with significant free energy (− 6.6 ΔG (kJ mol‒1) at pose 1. Here none H-bonding interactions were noticed with Gly724, Gly723, Pro729, Ile797, Lys794, Glu793, Lys769, Leu791 amino acidTyr801 which interacted through vandervaal’s, π - π, π –cation and halogen π-alkyl interactions (Fig. 8; Table 5).
Intermolecular interactions, such as hydrogen bonding and various hydrophobic interactions (such as π-amide, π- π, π-alkyl, π -cation / anion, and π- σ), play a crucial role in determining the stability and structure of proteins. These interactions are of great significance in understanding the therapeutic effects of proteins [53–54]. Further, the stability of the host-guest complex is determined by the hydrogen-bonding interaction. Multiple hydrophobic interactions present in various conformers compete with hydrogen bonding interactions, leading to a reduction in binding energy [55]. Our research revealed that the interactions were mostly governed by both hydrogen and hydrophobic forces, which significantly contribute to the therapeutic effectiveness of the tested chemical. Interactions of this nature are crucial for maintaining the stability and proper folding of proteins, which in turn ensures the protein remains stable and biologically functional [56].
Biological Evaluation
Antimicrobial Activities (MICs against standard strains)
Different pyrimidine base drug analogue were synthesized and their MIC was determined against standard strains including E. coli, P. aeruginosa, S.aureus and K. penumoniae using resazurin based 96 well micro-plate method. It was observed that all the synthetic analogues inhibited bacterial growth and in case of E. coli DMPN presented highest activity (MIC 1.56 µg/mL), whereas slightly higher activity was noticed against P. aeruginosa, S. aureus and K. penumoniae (MIC 3.12 µg/mL). Compound BrPN also presented significant inhbiotin against all strains (MIC range 3.12–1.56 µg/mL), however slightly higher similar inhibition was recorded in case of tBuBPN (MIC range 25–50 µg/mL) (Table 6).
| Compound | MIC µg/mL | |||
|---|---|---|---|---|
| E.coli | Pseudomonas aeruginosa | S.aureus | Klebsiella pneumoniae | |
| DMPN | 0.78 | 1.56 | 1.56 | 1.56 |
| BrPN | 1.56 | 3.12 | 3.12 | 1.56 |
| tBuBPN | 50.0 | 25.0 | 25.0 | 25.0 |
| Ciprofloxacin | 3.12 | 1.56 | 1.56 | 3.12 |
Antimicrobial Activities (MICs against clinical oral strains)
The synthesized compounds were screened against clinical pathogens including Pseudomonas aeruginosa, Bacillus chungangensis1, Bacillus paramycoides, Bacillus chungangensis2 and Paenibacillus dendritiformis. It was noticed that DMPN presented significant inhibition of all bacterial strains (MIC range 1.56–6.24 µg/mL). compounds BrPN also presented significant against all resistant strain (MIC range 6.24–49.2 µg/mL) Similarly tBuBPN was active only against Pseudomonas aeruginosa (MIC 1.56–6.24 µg/mL) (Table 7). A strong inhibition of bacteria was generally attributed to presence of diversified function groups in the structure analogues of pyridine [57]. The Substitution on pridine nucleus faciliatet interaction of molecule and boost its antimicrobial and antiviral properties [58].
| Compound | Pseudomonas aeruginosa | Bacillus chungangensis1 | Bacillus paramycoides | Bacillus chungangensis2 | Paenibacillus dendritiformis |
|---|---|---|---|---|---|
| DMPN | 1.56 | 6.24 | 3.12 | 1.56 | 3.12 |
| BrPN | 6.24 | 49.2 | 3.12 | 12.4 | 6.24 |
| tBuBPN | 6.24 | Inactive | 12.4 | Inactive | Inactive |
| Standard | 3.12 | 6..24 | 1.56 | 1.56 | 1.56 |
| Ciprofloxacin was used as standard drug | |||||
Antibiofilm and anti Quorum sensing activities
The antibiofilm activities of structural analogues revealed that DMPN (60-70.2%) and BrPN (41.2–58.6%) were able to present significant antibiofilm potential against all tested strains (Fig. 9), Whereas tBuBPN presented no activity to moderate inhibition of bacterial biofilms products by clinical strains (Fig. 9). The entire pyrimidine base synthetic drug analogues were used for anti-quorum sensing activity against Chromobacterium voilaceum. It was found that the synthetic pyrimidine base drug analogues were active against Chromobacterium voilaceum but DMPN and tBuBPN presented highest (14 ± 1.4 mm) antiquorum sensing activity, followed by tBuBPN (12 ± 1.6 mm). In violacine inhibition assay, both DMPN (57.0 ± 0.8%) and tBuBPN (56.4 ± 1.5%) showed moderate inhibition of violacine formation whereas low inhibition levels (54.0 ± 1.6%) were recorded in case BrPN (Table 8; Fig S13). A significant antibiofilm and anti-QS potential was attributed to presence of pyridine backbone with diversified functional groups that may inhibit the Biofilm formation and quorum sensing as reported earlier [59].
| Tested Molecule | Zone of inhibition (mm) | % Violacine inhibition |
|---|---|---|
| DMPN | 14 ± 1.4 | 57.0 ± 0.8% |
| BrPN | 12 ± 1.6 | 54.0 ± 1.6% |
| tBuBPN | 14 ± 0.7 | 56.4 ± 1.5% |
| Standard | 18.2 ± 0.5 | 71.2 ± 1.2 |
The current study describes the effective synthesis of numerous novel nicotinaldehyde derivatives in moderate to good yield by using the Suzuki cross-coupling reaction of 2-Chloro-3-nicotinaldehyde with different aryl boronic acids, which is catalysed by Pd. They were identified by NMR, FT-IR, and UV-VIS. Additionally, the experimental results and the results of the DFT analysis were compared. The computed result of 1H NMR, UV-Visible and Frequency present good agreement with experimental result which is apparent evidence for the conformation of synthesis of title compounds. Computational analysis showed Best interaction with targets and all compounds followed drug likeness rules. Among tested compounds, DMPN and tBuBPN presenetd significant antimicrobial, antibiofilm and anti Qs activities.
Supplementary Information
Supplementary material is attached as separate file
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Competing interests
The authors declare no competing interests.
Funding
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Author Contribution
AA: design of the work, writing the chemistry and biology part: AU, MA, and UA performed synthesis of the target compounds and interpretation of spectral data: FU, SOR, MA, writing the chemistry part: AA, UA, SOR and RA, revise the manuscript AU, NU, SA: Biological evaluation: AA, AU, QA Design the rational, Molecular docking and interpretation the biological result.
Acknowledgements
The authors extend their appreciation to University Higher Education Fund for funding this research work under Research Support Program for Central labs at King Khalid University through the project number CL/CO/B/5.
Data availability
This article contains all data.
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No competing interests reported.