L→S Coordination Complexes Containing Benzothiazol-2-ylidene Ligand: Quantum Chemical Analysis and Synthesis.

(NHC)→E coordination interactions were known where NHC is an N-heterocyclic carbene, and E is a main group element (B, C, N, Si, P). Recently, it was suggested that compounds with (NHC)→S coordination chemistry are also possible. This work reports quantum chemical analysis and synthesis of (NHC)→S-R(+) complexes in which benzothiazol-2-ylidene acts as a ligand. A Density functional study established that (NHC)→S interaction can best be described as a coordination interaction. Synthetic efforts were made, initially, to generate divalent sulfur compounds containing benzothiazole substituents. N-alkylation of the heterocyclic ring in these sulfides using methyl triflate led to the generation of the desired products with (NHC)→S coordination chemistry, which involves the in situ generation of NHC ring ligands. The observed changes in the 13C NMR spectra, before and after methylation, confirmed the change in the electronic character of the C-S bond from a covalent character to a coordination character.

Molecular Property Diagnostic Suite for COVID-19 (MPDSCOVID-19): an open-source disease-specific drug discovery portal.

Molecular Property Diagnostic Suite (MPDS) was conceived and developed as an open-source disease-specific web portal based on Galaxy. MPDSCOVID-19 was developed for COVID-19 as a one-stop solution for drug discovery research. Galaxy platforms enable the creation of customized workflows connecting various modules in the web server. The architecture of MPDSCOVID-19 effectively employs Galaxy v22.04 features, which are ported on CentOS 7.8 and Python 3.7. MPDSCOVID-19 provides significant updates and the addition of several new tools updated after six years. Tools developed by our group in Perl/Python and open-source tools are collated and integrated into MPDSCOVID-19 using XML scripts. Our MPDS suite aims to facilitate transparent and open innovation. This approach significantly helps bring inclusiveness in the community while promoting free access and participation in software development. Availability & Implementation: The MPDSCOVID-19 portal can be accessed at https://mpds.neist.res.in:8085/.

Identification of ethyl-6-bromo-2((phenylthio)methyl)imidazo[1,2-a]pyridine-3-carboxylate as a narrow spectrum inhibitor of Streptococcus pneumoniae and its FtsZ.

Filamentous temperature-sensitive mutant Z (FtsZ) is a key cell-division protein recognized as an important target for anti-bacterial drug discovery, especially in the context of rising multi-drug resistance. A respiratory pathogen, Streptococcus pneumoniae, is rapidly evolving antibiotic resistance, thus posing a clinical risk in the developing world. Inhibiting the conserved protein FtsZ, leading to the arrest of cell division, is an attractive alternative strategy for inhibiting S. pneumoniae. Previously, Vitamin K3 was identified as an FtsZ-targeting agent against S. pneumoniae. In the present work, docking studies were used to identify potential anti-FtsZ agents that bind to the Vitamin K3-binding region of a homology model generated for S. pneumoniae FtsZ. Compounds with imidazo[1,2-a]pyridine-3-carboxylate core were synthesized and screened for their anti-proliferative activity against S. pneumoniae. Remarkably, the hit compound IP-01 showed anti-bacterial action against S. pneumoniae without any activity on other bacteria. In S. pneumoniae, IP-01 showed similar inhibitory action on FtsZ and cell division as Vitamin K3. Sequence alignment identified three unique residues within S. pneumoniae FtsZ that IP-01 binds to, providing a structural basis for the observed specificity. IP-01 is one of the first narrow-spectrum agents identified against S. pneumoniae that targets FtsZ, and we present it as a promising lead for the design of narrow-spectrum anti-FtsZ anti-pneumococcal compounds.

Effect of Differential Surface Anisotropy on Dissolution Behavior of Fenofibrate Crystal Habits: Comparative Study using USP Type 2 and Type 4 Dissolution Apparatuses.

The solid-state properties of active pharmaceutical ingredient (API) have significant impact on its dissolution performance. In the present study, two different crystal habits viz. rod and plate shape of form I of FEN were evaluated for dissolution profile using USP Type 2 and Type 4 apparatuses. Molecular basis of differential dissolution performance of different crystal habits was investigated. Rod (FEN-R) and plate (FEN-P) shaped crystal habits of Form I of FEN were generated using anti-solvent crystallization method. Despite the same polymorphic form and similar particle size distribution, FEN-P demonstrated higher dissolution performance than FEN-R. Crystal face indexation and electrostatic potential (ESP) map provided information on differential relative abundance of various facets and their molecular environment. In FEN-R, the dominant facet (001) is hydrophobic due to the exposure of chlorophenyl moiety. Whereas, in FEN-P the dominant facet (01-1) was hydrophilic due to the presence of chlorine and ester carbonyl groups. Deeper insight on the impact of different facets on dissolution behavior was obtained by energy framework analysis by unveiling strength of intermolecular interactions along various crystallographic facets. Moreover, type 4 apparatus provided higher discriminatory ability over USP Type 2 apparatus, in probing the crystal habit induced differential dissolution performance of FEN. The findings of this study emphasize that crystal habit should be considered as an important critical material attribute (CMA) during formulation development of FEN and due considerations should be given to the selection of the appropriate dissolution testing set-up for establishing in vitro-in vivo correlation.

Synthesis of 3-sulfenylindole derivatives from 4-hydroxy-2H-chromene-2-thione and indole using oxidative cross-dehydrogenative coupling reaction and anti-proliferative activity study of some of their sulfone derivatives.

The synthesis of hitherto unreported 3-sulfenylindole derivatives is achieved from 4-hydroxy-2H-chromene-2-thione (1) and indole (2) by employing an oxidative cross-dehydrogenative coupling reaction using a combination of 10 mol% of molecular iodine and 1 equivalent of TBHP in DMSO at room temperature. Then, the 3-sulfenylindole derivatives 3a, 3b, 3d, 3f, 3 h, and 3 k were converted into their corresponding sulfone derivatives because of lead likeness properties. Subsequently, a target prediction and docking study of six sulfone derivatives (5a-f) was performed, and four sulfones, namely 5a, 5d, 5e, and 5f, were selected for further in-vitro studies. The four sulfones mentioned above exhibited prominent anti-proliferative activity on breast cancer (MCF7) cell lines. In addition, this reaction was exergonic through quantum chemical analysis of the mechanistic steps. The salient features of this reaction are mild reaction conditions, good yields, and broad substrate scope.

Effect of Deep Eutectic System (DES) on Oral Bioavailability of Celecoxib: In Silico, In Vitro, and In Vivo Study.

Different deep eutectic systems (DES) of choline chloride (CC)-urea (UA) (1:2), CC-glycerol (GLY) (1:2), CC-malonic acid (MA) (1:1), and CC-ascorbic acid (AA) (2:1) were generated and characterized by polarized light microscope (PLM) and Fourier transform infrared spectroscope (FTIR). The equilibrium solubility of celecoxib (CLX) in DES was compared to that in deionized water. The CC-MA (1:1) system provided ~10,000 times improvement in the solubility of CLX (13,114.75 µg/g) and was used for the generation of the CLX-DES system. The latter was characterized by PLM and FTIR to study the microstructure and intermolecular interaction between the CLX and CC-MA (1:1) DES. FTIR demonstrated the retention of the chemical structure of CLX. In vitro drug release studies in FaSSIF initially demonstrated high supersaturation, which decreased by ~2 fold after 2 h. Density functional theory (DFT)-based calculations provided a molecular-level understanding of enhanced solubility. Gibbs free energy calculations established the role of the strongest binding of CLX with CC and MA. A phase solubility study highlighted the role of hydrotropy-induced solubilization of the CLX-DES system. Animal pharmacokinetic studies established 2.76 times improvement in Cmax, 1.52 times reduction in tmax, and 1.81 times improvement in AUC0-∞. The overall results demonstrated the potential of developing a DES-based supersaturating drug-delivery system for pharmaceutical loading of drugs having solubility and dissolution rate-limited oral bioavailability.

Bronsted Acid-Catalyzed Regioselective Carboxamidation of 2-Indolylmethanols with Isonitriles.

A regioselective direct carboxamidation reaction of 2-indolylmethanols with readily available isocyanoesters/isocyanides has been reported in this work. The reaction was catalyzed by Bronsted acid such as p-TsOH to deliver the benzylic regioselective amides in 67-86% yield under mild conditions. The developed methodology provides alternative access to traditional metal-free carboxamidation via C-C and C-O bond formation with high atom economy. Furthermore, the developed approach was diversified to synthesize chiral indole-2-carboxamide derivatives with a moderate enantiomeric excess (61-73% ee) using an (R)-chiral phosphoric acid.

Identification of CYP3A4 inhibitors as potential anti-cancer agents using pharmacoinformatics approach.

Biguanide derivatives exhibit a wide variety of therapeutic applications, including anti-cancer effects. Metformin is an effective anti-cancer agent against breast cancer, lung cancer, and prostate cancer. In the crystal structure (PDB ID: 5G5J), it was found that metformin is found in the active site of CYP3A4, and the associated anti-cancer effect was explored. Taking clues from this work, pharmacoinformatics research has been carried out on a series of known and virtual biguanide, guanylthiourea (GTU), and nitreone derivatives. This exercise led to the identification of more than 100 species that exhibit greater binding affinity toward CYP3A4 in comparison to that of metformin. Selected six molecules were subjected to molecular dynamics simulations, and the results are presented in this work.

Iodocycloisomerization/Nucleophile Addition Cascade Transformations of 1,2-Alkynediones.

A general electrophilic iodocyclization/nucleophile addition cascade transformation for 1,2-alkynediones for the synthesis of various oxygen heterocycles and access to regioselective alkyne hydroxylation is reported. Furan-tethered ynediones resulted in the construction of exo-enol ethers via carbonyl-alkyne cyclization-initiated heteroarene dearomatization, whereas other (hetero)arene-, alkenyl-, and alkyl-tethered ynediones resulted in the formation of highly functionalized 3(2H)-furanones. Importantly, the developed domino protocols involve the construction of important heterocyclic scaffolds and installation of two functional groups in a single operation. Moreover, the use of water as a nucleophile resulted in regioselective alkyne hydroxylation via furanone ring opening. The developed protocols are characterized by a wide substrate scope, and their utility has been demonstrated by a number of postsynthetic transformations.

Importance of tautomerism in drugs.

Tautomerism is an important phenomenon exhibited by many drugs. As we discuss in this review, identifying the different tautomers of drugs and exploring their importance in the mechanisms of drug action are integral components of current drug discovery. Nuclear magnetic resonance (NMR), infrared (IR), ultraviolet (UV), Raman, and terahertz spectroscopic techniques, as well as X-ray diffraction, are useful for exploring drug tautomerism. Quantum chemical methods, in association with pharmacoinformatics tools, are being used to evaluate tautomeric preferences in terms of energy effects. Desmotropy (i.e., tautomeric polymorphism) of the drugs is particularly important in drug delivery studies.

The importance of four-membered NHCs in stabilizing Breslow intermediates on benzoin condensation pathway.

N-heterocyclic carbenes (NHCs) have been established to be effective organocatalysts for facilitating the benzoin condensation and many other reactions. These reactions involve the formation of a Breslow intermediate (BI), which exhibits umpolung chemistry. To facilitate organocatalysis, several new cyclic carbenes are being introduced, four-membered NHCs are of special interest. Whether these NHCs can exhibit catalytic influence or not, can be evaluated by exploring the potential energy surface (PES) of the benzoin condensation reaction. Quantum chemical analysis has been carried out to compare the PES of these four-membered NHCs with that of standard five-membered NHCs to explore their catalytic ability. The barrier for the first step of the reaction for the formation of BI is comparable in all the cases. But the barrier for the second step of the reaction leading to the benzoin formation from BI is estimated to be very high for the four membered NHCs. These results indicate that the probability of identifying and isolating the BI is very high in comparison to the completion of benzoin condensation reaction in the case of the four-membered NHCs.

High dose nanocrystalline solid dispersion powder of voriconazole for inhalation.

In the current work, we aimed to deliver high dose of voriconazole (VRC) to lung through dry powder for inhalation (DPIs). Furthermore, the research tested the hypothesis that drug nanocrystals can escape the clearance mechanisms in lung by virtue of their size and rapid dissolution. High dose nanocrystalline solid dispersion (NCSD) based DPI of VRC was prepared using a novel spray drying process. Mannitol (MAN) and soya lecithin (LEC) were used as crystallization inducer and stabilizer, respectively. The powders were characterized for physicochemical and aerodynamic properties. Chemical interactions contributing to generation and stabilization of VRC nanocrystals in the matrix of MAN were established using computational studies. Performance of NCSD (VRC-N) was compared with microcrystalline solid dispersion (VRC-M) in terms of dissolution, uptake in A549 and RAW 264.7 cells. Plasma and lung distribution of VRC-N and VRC-M in Balb/c mice upon insufflation was compared with the intravenous product. In VRC-N, drug nanocrystals of size 645.86 ± 56.90 nm were successfully produced at VRC loading of 45%. MAN created physical barrier to crystal growth by interacting with N- of triazole and F- of pyrimidine ring of VRC. An increase in drug loading to 60% produced VRC crystals of size 4800 ± 200 nm (VRC-M). The optimized powders were crystalline and showed deposition at stage 2 and 3 in NGI. In comparison to VRC-M, more than 80% of VRC-N dissolved rapidly in around 5-10 mins, therefore, showed higher and lower drug uptake into A549 and RAW 264.7 cells, respectively. In contrast to intravenous product, insufflation of VRC-N and VRC-M led to higher drug concentrations in lung in comparison to plasma. VRC-N showed higher lung AUC0-24 due to escape of macrophage clearance.

Drug-dendrimer complexes and conjugates: Detailed furtherance through theory and experiments.

Dendritic nanovectors-based drug delivery has gained significant attention in the past couple of decades. Dendrimers play a crucial role in deciding the solubility of sparingly soluble drug molecules and help in improving pharmacokinetics. A few important steps in drug delivery through dendrimers, such as drug encapsulation, formulation, and target-specific delivery, play an important role in deciding the fate of a drug molecule. It is also of prime importance to understand the interactions between a drug molecule and dendrimers at atomistic levels to decode the mechanism of action of drug-dendrimer complexes and their reliability in terms of drug delivery. Colossal progress in current experimental and computational approaches in the field has resulted in a vast amount of data that needs to be curated to be further implemented efficiently. Improved computational power has led to greater accuracy and prompt predictions of properties of drug-dendrimer complexes and their mechanism of action. The current review encapsulates the pioneering work in the field, experimental achievements in terms of drug delivery, and newer computational techniques employed in the advancement of the field.

Understanding Poor Milling Behavior of Voriconazole from Crystal Structure and Intermolecular Interactions.

The study investigated the milling behavior of voriconazole (VRZ) subjected to particle size reduction using air jet mill at differential air pressures of 5, 6, 7, and 8 bar for five cycles at each pressure. The crystal structure of VRZ was probed for understanding the fracture behavior from crystal packing and intermolecular interactions using molecular modeling tools of attachment energy (Eatt), density functional theory, and energy framework analysis. Upon milling for different cycles, VRZ showed that size reduction from (D90) 20 to 9 µm and 100% particles could not be milled to sizes below 9 µm, with the increase in either the milling intensity or cycle. The milled samples retained the original crystal lattice as evident from consistent melting endotherm (Tm = 130.75 °C); heat of fusion (ΔHf = 96.52 J/g) values; and the plate-shaped morphology. The powder X-ray diffraction pattern of milled samples consistently showed characteristic peaks of stable form B of VRZ. The crystallographic plane (001) was found to be the most prominent slip and the cleavage plane due to least Eatt and weak noncovalent interactions (6.996 kJ/mol) between 3'H and 4'F functional groups of the neighboring planes. The predicted indentation hardness value of 228.67 MPa further indicated toward the plastic nature of VRZ crystals. Corroborating outcomes from the different molecular modeling tools for VRZ, cleavage along the plane (001) was determined to be energetically favorable, whereas cleavage of isotropic 2D molecular sheets was energetically unfavorable. As milling proceeds and crystal reduces in size, contact surface area and overall interaction energy decrease contributing to plastic behavior of the crystal. It was concluded that crystal plasticity and isotropic 2D molecular sheets along with the orientation of particles to the direction of stress and attrition energy during air jet milling are contributing factors for nonuniform size reduction of VRZ particles.

Remdesivir: Mechanism of Metabolic Conversion from Prodrug to Drug.

BACKGROUND: Remdesivir (GS-5734) has emerged as a promising drug during the challenging times of COVID-19 pandemic. Being a prodrug, it undergoes several metabolic reactions before converting to its active triphosphate metabolite. It is important to establish the atomic level details and explore the energy profile of the prodrug to drug conversion process. METHODS: In this work, Density Functional Theory (DFT) calculations were performed to explore the entire metabolic path. Further, the potential energy surface (PES) diagram for the conversion of prodrug remdesivir to its active metabolite was established. The role of catalytic triad of Hint1 phosphoramidase enzyme in P-N bond hydrolysis was also studied on a model system using combined molecular docking and quantum mechanics approach. RESULTS: The overall energy of reaction is 11.47 kcal/mol exergonic and the reaction proceeds through many steps requiring high activation energies. In the absence of a catalyst, the P-N bond breaking step requires 41.78 kcal/mol, which is reduced to 14.26 kcal/mol in a catalytic environment. CONCLUSION: The metabolic pathways of model system of remdesivir (MSR) were explored completely and potential energy surface diagrams at two levels of theory, B3LYP/6-311++G(d, p) and B3LYP/6-31+G(d), were established and compared. The results highlight the importance of an additional water molecule in the metabolic reaction. The PN bond cleavage step of the metabolic process requires the presence of an enzymatic environment.

Molecular docking and molecular dynamics to identify collagenase inhibitors as lead compounds to address osteoarthritis.

Osteoarthritis (OA) is a degenerative disease which affects a large number of individuals. Collagenases, which belong to a class of metalloproteases (MMPs), are responsible for the degradation of cartilage manifested in OA. Inhibition of the catalytic domains of these MMPs is one of the important therapeutic strategies proposed for the prevention of OA. The main objective of this work is to evaluate the binding of curcumin and its metabolites with the active sites of collagenases in comparison to standard inhibitors on the basis of our hypothesis that curcumin/metabolites could exhibit an inhibitory effect on MMPs. Here, we report the molecular docking analysis of curcumin and its metabolites with collagenases (MMP-1, MMP-8, MMP-13). Among the molecules tested, curcumin monoglucuronide (CMG) demonstrated the best binding affinity with MMP-13, which is specifically implicated in OA. The CMG-MMP-complexes were further subjected to molecular dynamic simulations to explore the stability of the complexes and to estimate the free binding energies. The results indicated that CMG preferentially bind to MMP-13 in comparison to that of MMP-1 and MMP-8 with binding free energies (ΔGbind) of (-60.55), (-27.02) and (-46.91) kcal/mol, respectively. This is the first study which suggests that curcumin monoglucuronide can be considered as an effective lead compound to prevent the progression of OA.Communicated by Ramaswamy H. Sarma.

Identification of selective LdDHFR inhibitors using quantum chemical and molecular modeling approach.

Among the various known targets for the treatment of Leishmaniasis, dihydrofolate reductase (DHFR) is an essential target which plays an important role in the folate metabolic pathway. In the current study, pharmacoinformatics approaches including quantum chemistry methods, molecular docking and molecular dynamics simulations have been utilized to identify selective Leishmania donovani DHFR (LdDHFR) inhibitors. Initially, for the design of new LdDHFR inhibitors, a virtual combinatorial library was created by considering various head groups (scaffolds), linkers and tail groups. The scaffolds utilized in the library design were selected on the basis of their proton affinity (PA) estimated using quantum chemical methods, required to make a strong H-bond interaction with negatively charged LdDHFR active site. Later on, molecular docking-based virtual screening was performed to screen the designed library. Selectivity of the chosen hits toward the LdDHFR was established through re-docking in the human DHFR enzyme (HsDHFR). Best five hits were subjected to molecular dynamics (MD) simulations to validate their selectivity as well as stability in LdDHFR. Out of the five hits, four were found to be energetically more favorable and promising for selective binding toward LdDHFR in comparison to HsDHFR.Communicated by Ramaswamy H. Sarma.

Analytical developments of p-hydroxy prenylamine reference material for dope control research: Characterization and purity assessment.

Prenylamine was initially used for the treatment of angina pectoris and later on withdrawn from the market in 1988 due to cardiac arrhythmias concern. The major phase I metabolite of prenylamine is p-hydroxy prenylamine that has a chiral center in the structure. Even though p-hydroxy prenylamine was synthesized earlier, it lacked complete analytical developments for chiral high-performance liquid chromatography (HPLC) separation. However, p-hydroxy prenylamine reference material is not commercially available. The innovation of this manuscript is the development and validation of a chiral HPLC separation method and more extensive characterization of the reference material than previously reported method. Therefore, it was hypothesized to develop and validate normal phase HPLC method for p-hydroxy prenylamine reference material. p-Hydroxy prenylamine was synthesized in two batches and characterized successfully using 13 C NMR, 1 H NMR, high-resolution mass spectrometry (HRMS), Fourier transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). A normal phase chiral HPLC method was developed to analyze the p-hydroxy prenylamine purity. Separation of the p-hydroxy prenylamine enantiomers were achieved using ultra-high-performance liquid chromatography (UHPLC) on a ChiralCel ODH column at wavelength of 220 nm. The developed method was validated in terms of its linearity, accuracy, precision, and robustness for purification, purity assessment, and stability studies. Proton and carbon peaks were confirmed by nuclear magnetic resonance (NMR) analysis. Functional groups were confirmed by FT-IR. Loss on drying was 0.3% and 0.6% for Batches 1 and 2, respectively. The purity of the developed reference material for Batches 1 and 2 was found to be 99.59% and 100%, respectively. Therefore, the synthesized batches of p-hydroxy prenylamine can be used in dope testing as reference material.

Thiazetidin-2-ylidenes as four membered N-heterocyclic carbenes: theoretical studies and the generation of complexes with N+ center.

Thiazetidin-2-ylidenes have been designed as four membered N-heterocyclic carbenes (NHCs) using quantum chemical studies. These species are smaller analogs of thiazol-2-ylidenes, possess high singlet stability (57 kcal mol-1) and large nucleophilicity (3.4 eV). The possible existence of these carbenes has been established by synthesizing and crystalizing compounds with NHC→N+←(thiazetidin-2-ylidene) coordination bonds.

1,1-Diaminoazines as organocatalysts in phospha-Michael addition reactions.

1,1-Diaminoazines can act as effective organocatalysts for the formation of phosphorus-carbon bonds between biphenylphosphine oxide and an activated alkene (Michael acceptor). These catalysts provide the P-C adducts at a faster rate and with relatively better yields in comparison to the organocatalysts employed earlier. The notable advantage is that 1,1-diaminoazines catalyse the reaction even in an aqueous medium with very good yields. Organocatalysis using 1,1-diaminoazines was also successfully carried out between dimethylphosphite and benzylidenemalononitrile under multicomponent conditions.