Manganese matere bonds in biological systems: PDB inspection and DFT calculations.

A Protein Data Bank (PDB) survey has revealed noncovalent contacts involving Mn centres and protein residues. Their geometrical features are in line with the interaction between low electron density sites located along the Mn-O/N coordination bonds (σ-holes) and the lone pairs belonging to TYR, SER or HIS residues, known as a matere bond (MaB). Calculations at the PBE0-D3/def2-TZVP level of theory were used to investigate the strength and shed light on the physical nature of the interaction. We expect the results presented herein will be useful for those scientists working in the fields of bioinorganic chemistry, particulary in protein-metal docking, by providing new insights into transition metal⋯Lewis base interactions as well as a retrospective point of view to further understand the structural and functional implications of this key transition metal ion.

Thio and Seleno-Psoralens as Efficient Triplet Harvesting Photosensitizers for Photodynamic Therapy.

The Psoralen (Pso) molecule finds extensive applications in photo-chemotherapy, courtesy of its triplet state forming ability. Sulfur and selenium replacement of exocyclic carbonyl oxygen of organic chromophores foster efficient triplet harvesting with near unity triplet quantum yield. These triplet-forming photosensitizers are useful in Photodynamic Therapy (PDT) applications for selective apoptosis of cancer cells. In this work, we have critically assessed the effect of the sulfur and selenium substitution at the exocyclic carbonyl (TPso and SePso, respectively) and endocyclic oxygen positions of Psoralen. It resulted in a significant redshifted absorption spectrum to access the PDT therapeutic window with increased oscillator strength. The reduction in singlet-triplet energy gap and enhancement in the spin-orbit coupling values increase the number of intersystem crossing (ISC) pathways to the triplet manifold, which shortens the ISC lifetime from 10-5 s for Pso to 10-8 s for TPso and 10-9 s for SePso. The intramolecular photo-induced electron transfer process, a competitive pathway to ISC, is also considerably curbed by exocyclic functionalizations. In addition, a maximum of 115 GM of two-photon absorption (2PA) with IR absorption (660-1050 nm) confirms that the Psoralen skeleton can be effectively tweaked via single chalcogen atom replacement to design a suitable PDT photosensitizer.

Critical assessment of interactions between ct-DNA and choline-based magnetic ionic liquids: evidences of compaction.

Ionic liquids (ILs) have become an alternative green solvent for storage and for stability of DNA. However, an in-depth understanding of binding and molecular interactions between ILs and DNA is needed. In this respect, magnetic ILs (MILs) are promising due to their tunable physicochemical properties. Various spectroscopic techniques and molecular simulations have been employed to unravel the critical factors of the strength and binding mechanism of MILs with DNA. UV-vis spectra unravel the multimodal binding of MILs with DNA, and the intrusion of IL molecules into the minor groove of DNA has been observed from dye displacement studies. Fluorescence correlation spectroscopic studies and scanning electron microscopy confirm the compaction of the DNA. ITC and molecular docking studies estimate the binding affinity of DNA with MILs, of ∼7 kcal mol-1. The 1 µs long-MD simulations give insight into the structural changes in the DNA in the MIL environment. Due to strong interaction with choline ions in the close vicinity, DNA helixes bend or squeeze in length and dilate in diameter (elliptical → spherical), leading to compaction. The post-MD parameters suggest a stronger interaction with [Ch]2[Mn] IL than with [Ch][Fe] IL; hence, the former induces DNA compaction to a more significant extent. Furthermore, decompaction is observed with the addition of sodium salts and is characterized using spectroscopic methods.

Covalent Organic Frameworks as Nano-Reservoir for Room Temperature RNA Storage.

The emerging role of Ribonucleic acids (RNAs) as therapeutics is alluring. However, RNAs are extremely labile under ambient conditions and typically need to be stored in cryogenic conditions (-20 °C to -80 °C). Hence, storage, stabilization, and transportation of RNA under ambient conditions have been an arduous task and remain an unsolved problem. In this work, a guanidinium-based ionic covalent organic framework (COF), TTGCl with nanotubular morphology, was synthesized and used as nano-reservoirs for room-temperature storage of RNA. To understand the role of the nanotubular morphology and chemical nature of TTGCl in stabilizing the RNA structure and for comparison purposes, a neutral COF, TMT-TT, is synthesized and studied. Further, density functional theory (DFT) studies confirmed non-covalent interaction between the COFs and the RNA nucleobases, facilitating reversible storage of RNA. RNA loaded in COFs was found to be resistant to enzymatic degradation when treated with RNase. Gel electrophoresis and sequencing confirmed the structural integrity of the recovered RNAs and their further processibility.

Onset of Nitriles Hydration with an Environmentally Benign Catalyst: in-Water versus on-Water Conditions.

The reaction yield of nitriles hydration using a catalyst depends on the aqueous medium. Using ab initio molecular dynamics, we probed whether "in-water" (in bulk medium) or "on-water" (at the interface with vacuum) conditions can change the onset of the reaction. Investigating a hydrogen-bond mediated mechanism, the lifetimes of the intermolecular interaction between benzonitrile and choline in the two protocols were compared, and the diffusion of the hydroxide anion around the cyano group was discussed.

Critical assessment of selenourea as an efficient small molecule fluorescence quenching probe to monitor protein dynamics.

Organoselenium compounds have recently been the experimentalists' delight due to their broad applications in organic synthesis, medicinal chemistry, and materials science. Selenium atom replacement of the carbonyl oxygen of the urea moiety dramatically reduces the HOMO-LUMO gap and oxidation potential, which completely changes the physicochemical properties of selenocarbonyl compounds. To our surprise, the photophysics and utility of a simple molecule such as selenourea (SeU) have not been explored in detail, which persuaded us to investigate its role in excited state processes. The steady-state emission, temperature-dependent time-correlated single photon counting, and femtosecond fluorescence upconversion experimental results confirmed that SeU significantly enhances the fluorescence quenching through a photoinduced electron transfer (PET) mechanism with an ∼10 ps ultrafast intrinsic PET lifetime component which is mostly absent in thiourea (TU). A wide range of fluorophores, based on their different redox abilities and fluorescence lifetimes covering a broad spectral window (λex: 390-590 nm and λem: 490-690 nm), were chosen to validate the proof of the concept. It was extended to tetramethylrhodamine (TMR)-5-maleimide labeled lysozyme protein, where we observed significant fluorescence quenching in the presence of SeU. The present work emphasizes that the high quenching efficiency with an ultrafast PET process, reduced orbital energy gap, and higher negative free energy change of the electron transfer reaction are the representative characteristics of selenourea or selenoamides to enable them as potential surrogates of thioamides or oxoamides quenching probes to monitor protein conformational changes and dynamics.

Spodium Bonds Involving Methylmercury and Ethylmercury in Proteins: Insights from X-ray Analysis and Computations.

In this study, the stability, directionality, and physical nature of Spodium bonds (SpBs, an attractive noncovalent force involving elements from group 12 and Lewis bases) between methylmercury (MeHg) and ethylmercury (EtHg) and amino acids (AAs) have been analyzed from both a structural (X-ray analysis) and theoretical (RI-MP2/def2-TZVP level of theory) point of view. More in detail, an inspection of the Protein Data Bank (PDB) reported evidence of noncovalent contacts between MeHg and EtHg molecules and electron-rich atoms (e.g., O atoms belonging to the protein backbone and S atoms from MET residues or the π-systems of aromatic AAs such as TYR or TRP). These results were rationalized through a computational study using MeHg coordinated to a thiolate group as a theoretical model and several neutral and charged electron-rich molecules (e.g., benzene, formamide, or chloride). The physical nature of the interaction was analyzed from electrostatics and orbital perspectives by performing molecular electrostatic potential (MEP) and natural bonding orbital (NBO) analyses. Lastly, the noncovalent interactions plot (NCIplot) technique was used to provide a qualitative view of the strength of the Hg SpBs and compare them to other ancillary interactions present in these systems as well as to shed light on the extension of the interaction in real space. We believe that the results derived from our study will be useful to those scientists devoted to protein engineering and bioinorganic chemistry as well as to expanding the current knowledge of SpBs among the chemical biology community.

Effect of Choline Amino Acid-Based Ionic Liquids on Stability and Structure of Hemoglobin.

Ionic liquids (ILs) can stabilize or destabilize proteins, which motivates us to examine their effect on hemoglobin. The native state of hemoglobin (Hb) is disrupted at different physical conditions such as pressure, temperature, and solvents. Herein, we have monitored the stability of Hb in a nontoxic and biocompatible IL, i. e., choline amino acid-based Ils (ChAAILs), using various spectroscopic techniques like UV-Vis and fluorescence spectroscopy, circular dichroism (CD), and isothermal titration calorimetry (ITC) measurements. It was observed that Hb stays neither in its native state nor in its fully denatured state; rather, it achieves an intermediate state in the presence of ChAAILs. The research on the intermediate state of Hb is still unexplored. Research has been pursued to find a suitable ligand or IL that can stabilize the intermediate state of Hb. In that context, ChAAILs are among the best choices. Molecular docking studies unravel the binding of ChAAILs with Hb. The obtained binding energies of the docked complex are -7.2 kcal/mol and -8.7 kcal/mol for binding of Hb with [Chl][Gly] and [Chl][Met], respectively, which was in line with the ITC results. The quantum chemical calculations show that H-bond plays a significant role for the interaction between Hb and ChAAILs.

Tetrel bonds involving a CF3 group participate in protein-drug recognition: a combined crystallographic and computational study.

In this study, the ability of CF3 groups to bind to the electron-rich side chains and backbone groups of proteins has been investigated by combining a Protein Data Bank (PDB) survey and ab initio quantum mechanics calculations. More precisely, an inspection of the PDB involving organic ligands containing a CF3 group and electron-rich atoms (A = N, O and S) in the vicinity revealed 419 X-ray structures exhibiting CF3⋯A tetrel bonds (TtBs). In a posterior stage, those hits that exhibited the most relevant features in terms of directionality and intermolecular distance were selected for theoretical calculations at the RI-MP2/def2-TZVPD level of theory. Also, Hammett's regression plots of several TtB complexes involving meta- and para-substituted benzene derivatives were computed to shed light on the substituent effects. Moreover, the TtBs were characterized through several state-of-the-art computational techniques, such as the Quantum Theory of Atoms in Molecules (QTAIM) and Noncovalent Interactions plot (NCIplot) methodologies. We believe that the results gathered from our study will be useful for rational drug design and biological communities as well as for further expanding the role of this interaction to biomedical applications.

Intermolecular noncovalent interactions with carbon in solution.

One of the most familiar carbon-centered noncovalent interactions (NCIs) involving an antibonding π*-orbital situated at the Bürgi-Dunitz angle from the electron donor, mostly lone pairs of electrons, is known as n → π* interactions, and if it involves a σ* orbital in a linear fashion, then it is known as the carbon bond. These NCIs can be intra- or inter-molecular and are usually weak in strength but have a paramount effect on the structure and function of small-molecular crystals and proteins. Surprisingly, the experimental evidence of such interactions in the solution phase is scarce. It is even difficult to determine the interaction energy in the solution. Using NMR spectroscopy aided with molecular dynamics (MD) simulation and high-level quantum mechanical calculations, herein we provide the experimental evidence of intermolecular carbon-centered NCIs in solution. The challenge was to find appropriate heterodimers that could sustain room temperature thermal energy and collisions from the solvent molecules. However, after several trial model compounds, the pyridine-N-oxide:dimethyltetracyanocyclopropane (PNO-DMTCCP) complex was found to be a good candidate for the investigation. NBO analyses show that the PNO:DMTCCP complex is stabilized mainly by intermolecular n → π* interaction when a weaker carbon bond gives extra stability to the complex. From the NMR study, it is observed that the NCIs between DMTCCP and PNO are enthalpy driven with an enthalpy change of -28.12 kJ mol-1 and dimerization energy of ∼-38 kJ mol-1 is comparable to the binding energies of a conventional hydrogen-bonded dimer. This study opens up a new strategy to investigate weak intermolecular interactions such as n → π* interaction and carbon bonds in the solution phase.

Hydrogen Bonding Directed Reversal of 13 C NMR Chemical Shielding.

The deshielding or downfield 13 C NMR chemical shift of amide carbonyl carbon upon H-bonding is a widely observed phenomenon. This downfield shift is commonly used as a spectroscopic ruler for H-bonding. However, the very first observation of an upfield 13 C NMR of thiocarbonyl carbon in thioamides upon H-bonding encouraged us to explore the physical origin of the reversal of 13 C NMR chemical shielding. Careful NMR analysis shows that sulfur and selenium-centered H-bonds (S/SeCHBs) induce a shielding effect on the 13 CC=S(Se) while changing from amides to thioamides or selenoamides. In addition, natural chemical shielding (NCS) analysis shows that the σ11 and σ22 components of the isotropic shielding tensor (σ) have a crucial role in this unusual shielding.

Synthesis, Characterization, and the N Atom Transfer Reactivity of a Nitridochromium(V) Complex Stabilized by a Corrolato Ligand.

Metal complexes bearing nitrido ligands (M≡N) are at the forefront of current scientific research due to their resemblances with the metal complexes involved in the nitrogen fixation reactions. An oxo(corrolato)chromium(V) complex was used as a precursor complex for the facile synthesis of a new nitrido(corrolato)chromium(V) complex. The nitrido(corrolato)chromium(V) complex was characterized by various spectroscopic techniques. Density functional theory (DFT) calculations were performed on the nitrido(corrolato)chromium(V) complex to assign the vibrational and electronic transitions of this complex. The chromium-nitrogen (nitrido) bond distance obtained in the DFT-optimized structure is 1.530 Å and matches well with the earlier reported authentic Cr≡N bond distances obtained from the single-crystal X-ray diffraction data. This nitrido(corrolato)chromium(V) compound exhibited a sharp Soret band at 438 nm and a Q band at 608 nm. DFT calculations deliver that the origin of the bands at 438 and 608 nm is due to the intraligand charge transfer transitions. The nitrido(corrolato)chromium(V) complex showed one reversible oxidation and one reversible reduction couple at +0.53 and -0.06 V, respectively, vs the Ag/AgCl reference electrode. The simulation of the electron paramagnetic resonance data of the nitrido(corrolato)chromium(V) compound provided the following parameters: g iso = 1.987, A 53Cr = 26 G, and A 14N = 2.71 G. From all these analyses, we can conclude that the electronic configuration in the native state of nitrido(corrolato)chromium(V) can be best described as [(cor3-)CrV(N3-)]-. Reactions of nitrido(corrolato)chromium(V) with the chloro(porphyrinato)chromium(III) complex resulted in a complete intermetal N atom transfer reaction between chromium corrole and chromium porphyrin complexes. A second-order rate constant of 4.29 ± 0.10 M-1 s-1 was obtained for this reaction. It was also proposed that this reaction proceeds via a bimetallic µ-nitrido intermediate.

Thiolumazines as Heavy-Atom-Free Photosensitizers for Applications in Daylight Photodynamic Therapy: Insights from Ultrafast Excited-State Dynamics.

Finding appropriate photosensitizers (PSs) for daylight photodynamic therapy (dPDT) applications is extremely challenging, even though heavy-atom-free photosensitizers (HAFPSs) such as thiocarbonyl-modified nucleobases have shown a ray of hope. Few attempts have been made to find alternative natural products for dPDT applications. Pteridine heterocycles consisting of a pyrazine ring and a pyrimidine ring, such as lumazine, which exhibit many structural similarities to the alloxazine ring of the flavin molecule, could be an option for HAFPSs. The photophysical and quantum mechanical studies of the thio-modified lumazines revealed that sequential thiomodifications in lumazine result in a bathochromic shift. Additionally, higher tissue penetration depths were observed for thiolumazines. The fluorescence quenching in the case of thiomodified lumazines was explained using triplet state formation, whereas the contribution from the photoinduced electron transfer process cannot be ignored. It was also noticed that a strong one-photon absorption influenced the two-photon absorption (TPA) process, leading to a self-focusing effect in the visible spectral region. The higher tissue penetration and larger TPA cross section are the hallmark characteristics of the thiolumazines to be considered as potential HAFPSs for dPDT applications.

Hydrogen bonding with polonium.

Hydrogen bonding (H-bonding) with heavier chalcogens such as polonium and tellurium is almost unexplored owing to their lower electronegativities, providing us an opportunity to delve into the uncharted territory of X-H⋯Po/Te H-bonds (X-H, X = O, N, C). Employing high-level quantum mechanical calculations that include dispersion correction and the relativistic effect and considering dimethyl polonium (Me2Po) as the model H-bond donor, we have provided evidence of the X-H⋯Po H-bonds for the first time. The H-bond energies can be as much as 30 kJ mol-1, which is energetically comparable to any conventional H-bonds. It is counterintuitive from the perspective of low electronegativity of polonium but possible if one considers the contributions from polarizability, dispersion, and the relativistic effect. We strongly believe that these fundamental studies are expected to impact polonium chemistry, such as in marine science, as dimethyl polonium is one of the major chemicals produced by aerobic marine microorganisms and tracer applications of polonium for environmental carbon cycles.

Noncovalent interactions in proteins and nucleic acids: beyond hydrogen bonding and π-stacking.

Understanding the noncovalent interactions (NCIs) among the residues of proteins and nucleic acids, and between drugs and proteins/nucleic acids, etc., has extraordinary relevance in biomolecular structure and function. It helps in interpreting the dynamics of complex biological systems and enzymatic activity, which is esential for new drug design and efficient drug delivery. NCIs like hydrogen bonding (H-bonding) and π-stacking have been researchers' delight for a long time. Prominent among the recently discovered NCIs are halogen, chalcogen, pnictogen, tetrel, carbo-hydrogen, and spodium bonding, and n → π* interaction. These NCIs have caught the imaginations of various research groups in recent years while explaining several chemical and biological processes. At this stage, a holistic view of these new ideas and findings lying scattered can undoubtedly trigger our minds to explore more. The present review attempts to address NCIs beyond H-bonding and π-stacking, which are mainly n → σ*, n → π* and σ → σ* type interactions. Five of the seven NCIs mentioned earlier are linked to five non-inert end groups of the modern periodic table. Halogen (group-17) bonding is one of the oldest and most explored NCIs, which finds its relevance in biomolecules due to the phase correction and inhibitory properties of halogens. Chalcogen (group 16) bonding serves as a redox-active functional group of different active sites of enzymes and acts as a nucleophile in proteases and phosphates. Pnictogen (group 15), tetrel (group 14), triel (group 13) and spodium (group 12) bonding does exist in biomolecules. The n → π* interactions are linked to backbone carbonyl groups and protein side chains. Thus, they are crucial in determining the conformational stability of the secondary structures in proteins. In addition, a more recently discovered to and fro σ → σ* type interaction, namely carbo-hydrogen bonding, is also present in protein-ligand systems. This review summarizes these grand epiphanies routinely used to elucidate the structure and dynamics of biomolecules, their enzymatic activities, and their application in drug discovery. It also briefs about the future perspectives and challenges posed to the spectroscopists and theoreticians.

Investigation of the Nature of Intermolecular Interactions in Tetra(thiocyanato)corrolato-Ag(III) Complexes: Agostic or Hydrogen Bonded?

Tetra(thiocyanato)corrolato-Ag(III) complexes presented here constitute a new class of metallo-corrole complexes. The spectroscopic properties of these complexes are quite unusual and interesting. For example, the absorption spectra of these ß-substituted corrolato-Ag(III) complexes are very different from those of the ß-unsubstituted corrolato-Ag(III) derivatives. Single-crystal XRD analysis of a representative tetra(thiocyanato)corrolato-Ag(III) derivative reveals C-H···Ag interactions. The C-H···Ag interactions are rarely demonstrated in the crystal lattice of a discrete coordination/organometallic compound. Optimization of the hydrogen positions of the crystal structure discloses the geometrical parameters of the said interaction as a Ag···H distance of 2.597 Å and ∠C-H···Ag of 109.62°. The natural bond orbital analysis provides information about the donor-acceptor orbitals involved in the interactions and their interaction energies. It was observed that the σC-H orbital overlaps with the vacant d-orbital of Ag with an interaction energy of 17.93 kJ/mol. The filled d-orbital of Ag overlaps with the σ*C-H orbital with an interaction energy of 4.79 kJ/mol. The highlights of this work are that the H···Ag distance is outside of the distance range for the typical agostic interaction but fitted with the weak H-bond distance. However, the ∠C-H···Ag angle is within the range of the agostic interaction. Both crystallographic data and electronic structure calculations reveal that these kinds of intermolecular interactions in square-planar d8 Ag(III) complexes are intermediate in nature. Thus, they cannot be categorically called either hydrogen bonding or agostic interaction.

Carbon-Centered Hydrogen Bonds in Proteins.

Hydrogen bonding (H-bonding) without lone pair(s) of electrons and π-electrons is a concept developed 2-3 years ago. H-bonds involving less electronegative tetrahedral carbon are beyond the classical concept of H-bonds. Herein, we present the first report on H-bonds with tetravalent carbons in proteins. A special bonding arrangement is needed to increase the negative charge density around the sp3-hybridized carbon atom. Therefore, less electronegative elements such as As and Mg, when bonded to sp3-C, enable the C-atoms as H-bond acceptors. Careful protein structure analysis aided by several quantum chemical calculations suggests that these H-bonds are weak to moderate in strength. We developed an empirical equation to estimate the C-H···C H-bond energy in proteins from the distances between the C- and H-atoms. In proteins, the binding energies range from -5.4 to -14.0 kJ/mol. The C-H···C H-bonds assist the substrate binding in proteins. We also explored the potential role of these carbon-centered H-bonds in C-H bond activation through σ-bond metathesis. To our surprise, contribution from these H-bonds is almost of similar magnitude as that from C-H···π H-bonds for C-H bond activation.

Se⋠⋠⋠O/S and S⋠⋠⋠O Chalcogen Bonds in Small Molecules and Proteins: A Combined CSD and PDB Study.

The importance of selenium-centered noncovalent chalcogen bonds represented as Se⋅⋅⋅A (A=O/S) has been explored for short directional contacts in small molecules and proteins. In addition, S⋅⋅⋅O centered contacts have been analyzed. Computational analyses involving the quantitative assessment of the associated energetics, the molecular electrostatic potentials (MEP), and electron density derived topological parameters, namely, quantum theory of atom in molecules (QTAIM) analyses, and NBO (natural bond orbital) based calculations, have been performed to unequivocally establish the strength, stability, and attractive role of chalcogen bonds in the solid-state. This investigation has been performed in molecules from both the Cambridge Structural Database (CSD) and Protein Data Bank (PDB). Thus futuristic materials may be designed keeping in mind the significance of these interactions, including their relevance in biology.

Structural Dynamics of RNA in the Presence of Choline Amino Acid Based Ionic Liquid: A Spectroscopic and Computational Outlook.

Ribonucleic acid (RNA) is exceedingly sensitive to degradation compared to DNA. The current protocol for storage of purified RNA requires freezing conditions below -20 °C. Recent advancements in biological chemistry have identified amino acid-based ionic liquids as suitable preservation media for RNA, even in the presence of degrading enzymes. However, the mechanistic insight into the interaction between ILs and RNA is unclear. To the best of our knowledge, no attempts are made so far to provide a molecular view. This work aims to establish a detailed understanding of how ILs enable structural stability to RNA sourced from Torula yeast. Herein, we manifest the hypothesis of multimodal binding of IL and its minimal perturbation to the macromolecular structure, with several spectroscopic techniques such as time-resolved fluorescence and fluorescence correlation spectroscopy (FCS) aided with molecular dynamics at microsecond time scales. Relevant structural and thermodynamic details from biophysical experiments confirm that even long-term RNA preservation with ILs is a possible alternative devoid of any structural deformation. These results establish a unifying mechanism of how ILs are maintaining conformational integrity and thermal stability. The atomistic insights are transferable for their potential applications in drug delivery and biomaterials by considering the advantages of having maximum structural retention and minimum toxicity.

Gram-Scale Synthesis of 1,8-Naphthyridines in Water: The Friedlander Reaction Revisited.

The products of the Friedlander reaction, i.e., 1,8-naphthyridines, have far-reaching impacts in materials science, chemical biology, and medicine. The reported synthetic methodologies elegantly orchestrate the diverse synthetic routes of naphthyridines but require harsh reaction conditions, organic solvents, and expensive metal catalysts. Here, we introduce gram-scale synthesis of 1,8-naphthyridines in water using an inexpensive and biocompatible ionic liquid (IL) as a catalyst. This is the first-ever report on the synthesis of naphthyridines in water. This is a one-step reaction, and the product separation is relatively easy. The choline hydroxide (ChOH) is used as a metal-free, nontoxic, and water-soluble catalyst. In comparison to other catalysts reported in the literature, ChOH has the advantage of forming an additional hydrogen bond with the reactants, which is the vital step for the reaction to happen in water. Density functional theory (DFT) and noncovalent interaction (NCI) plot index analysis provide the plausible reaction mechanism for the catalytic cycle and confirm that hydrogen bonds with the IL catalyst are pivotal to facilitate the reaction. Molecular docking and molecular dynamics (MD) simulations are also performed to demonstrate the potentialities of the newly synthesized products as drugs. Through MD simulations, it was established that the tetrahydropyrido derivative of naphthyridine (10j) binds to the active sites of the ts3 human serotonin transporter (hSERT) (PDB ID: 6AWO) without perturbing the secondary structure, suggesting that 10j can be a potential preclinical drug candidate for hSERT inhibition and depression treatment.