Phenothiazine Derivatives Research Articles

Phenothiazine derivatives based on double benzylidene ketone structure: Application to red light photopolymerization

Two novel phenothiazine derivatives PTZs (PTZ-H and PTZ-C) with D-A configuration based on double benzylidene ketone structure were synthesized and showed good charge transfer capability. The absorption wavelength of PTZ-C formed by introducing aryl groups to both sides of PTZ-H can reach more than 620 nm. In photopolymerization, PTZ-C performed better than PTZ-H as a photosensitizer to sensitize iodonium salt (ONI) to initiate free radical photopolymerization (FRP) and cationic photopolymerization (CP) under 532 and 620 nm LED light source. The photochemical reaction processes between PTZs and ONI were studied by means of steady-state photolysis, UV–vis absorption, cyclic voltammetry (CV), and fluorescence quenching experiments.

Very sensitive probes for quantitative and organoleptic detection of oxygen based on conformer-induced room-temperature phosphorescence enhancement of the derivative of triazatruxene and phenothiazine

Organic materials which show room-temperature phosphorescence (RTP) are of interest for many applications including chemical qubits which are the core units of a quantum information systems, organic light emitting diodes, chemical sensors. In contrast to triplet emitters based on noble metals (e.g. Ir, Rh), quantum yields of RTP of noble-atom-free organic emitters are much lower than unity. In this work, we report on a new approach to conformer-induced RTP enhancement of organic triplet emitters. The synthesis, thermal, photophysical, charge-transporting and oxygen sensing properties of the derivative of phenothiazine and triazatriazatruxene in which phenothiazine moieties are linked to nitrogen atoms of triazatriazatruxene via C-2 positions are presented. This compound exhibit stable RTP with a quantum yield of 54% which is more than six times higher than that of a reference material. For 1% solid solution of the compound in Zeonex, the ratio of intensity of RTP observed under vacuum and fluorescence intensity recorded in air reached the value of 19 which allows quantitative detection of oxygen with the high Stern-Volmer quenching constant of 7.83 × 10−3 ppm−1. The observed change of emission colour depending on the oxygen concentration can be used for the simple detection of oxygen by human eye.

Phenothiazine derivatives of 1,8-naphthalic anhydride: Synthesis, characterization and antimicrobial studies

The following article describes the synthesis of phenothiazine derivatives of 1,8-naphthalic anhydride. The target compounds were prepared by an interaction of 6-(10H-phenothiazin-10-yl)-1H,3H-naphtho[1,8-cd]pyran-1,3-dione and its derivatives with H2O2, H2NNH2, HNO3/CH3COOH and HCl, respectively. The compounds obtained were spectroscopically characterized by IR, 1H NMR and 13C NMR including 13C DEPT 135. Their antimicrobial activity against Gram-positive and Gram-negative bacteria, yeasts and molds have also been studied.

Tri- and Pentacyclic Azaphenothiazine as Pro-Apoptotic Agents in Lung Carcinoma with a Protective Potential to Healthy Cell Lines.

The phenothiazine derivatives, tricyclic 10H-3,6-diazaphenothiazine (DPT-1) and pentacyclic 7-(3′-dimethylaminopropyl)diquinothiazine (DPT-2), have recently been shown to exhibit promising anticancer activities in vitro. In this report, we demonstrated that DPT-1 and DPT-2 could be pro-apoptotic agents in lung carcinoma, the human lung carcinoma A549 and non-small lung carcinoma H1299, in the range of IC50 = 1.52–12.89 µM, with a protective potential to healthy cell lines BEAS-2B and NHDF. The compounds showed higher activity in the range of the tested concentrations and low cytotoxicity in relation to normal healthy cells than doxorubicin, used as the reference drug. The cytostatic potential of DPT-1 and DPT-2 was demonstrated with the use of MTT assay. Cell cycle analysis via flow cytometry using Annexin-V assay showed the pro-apoptotic and pro-necrotic role of the studied diazaphenothiazines in the cell cycle. DPT-1 and DPT-2 initiated a biological response in the investigated cancer models with a different mechanism and at a different rate. Based on these findings, it can be concluded that DPT-1 and DPT-2 have potential as chemotherapeutic agents.

Does the change in the length of the alkyl chain bring us closer to the compounds with the expected photophysical and biological properties? – Studies based on D-π-D-A imidazole-phenothiazine system

The novel imidazole-based phenothiazine derivatives 3a-3e differing in the length of the alkyl chain at the imidazole substituents were effectively designed and synthesized. The effect of the alkyl chain on the photophysical properties of novel compounds was systematically investigated and supported by TD/DFT calculations. The photophysical characterization of 3a-3e compounds was performed in a series of solvents. Both absorption and fluorescence spectra exhibited positive solvatochromism. Phenothiazine derivatives 3a-3e have a noteworthy emission from blue to yellow region 450–600 nm, high quantum yields 41–93%, lifetimes in nanosecond scale (4.01–7.55 ns), and Stokes shifts in the range of 5688–7021 cm−1 in solvents of different polarity. The noticeable positive solvatochromism indicates the good charge separation in compounds. This work presents the variability of photophysical properties associated with a simple modification of the alkyl chain at the imidazole unit in 3a-3e compounds. Additionally, the ability of the novel compounds 3a-3e for cellular staining, and their cytotoxicity was investigated. Comparative lack of toxicity and appealing photophysical properties make them useful as molecular fluorescent dyes in biological applications.

Inhibition of dengue virus infection by trifluoperazine.

Dengue virus (DENV), a member of the genus Flavivirus, family Flaviviridae, is the most widespread viral pathogen transmitted to humans by mosquitoes. Despite the increased incidence of DENV infection, there are no antiviral drugs available for treatment or prevention. Phenothiazines are heterocyclic compounds with various pharmacological properties that are very adaptable for drug repurposing. In the present report, we analyzed the antiviral activity against DENV and the related Zika virus (ZIKV) of trifluoperazine (TFP), a phenothiazine derivative in clinical use as an antipsychotic and antiemetic agent. TFP exhibited dose-dependent inhibitory activity against the four DENV serotypes and ZIKV in monkey Vero cells at non-cytotoxic concentrations with 50% effective concentration values in the range 1.6-6.4 µM. A similar level of antiviral efficacy was exhibited by TFP against flavivirus infection in the human cell lines A549 and HepG2. Mechanistic studies, performed using time-dependent infectivity assays, real-time RT-PCR, Western blot, and immunofluorescence techniques, indicated that uncoating of the virus during penetration into the cell was the main target for TFP in infected cells, but the compound also exerted a minor effect on a late stage of the virus multiplication cycle. This study demonstrates that TFP, a pharmacologically active phenothiazine, is a selective inhibitor of DENV multiplication in cell culture. Our findings open perspectives for the repositioning of phenothiazines like TFP with a wide spectrum of antiviral efficacy as potential agents for the control of pathogenic flaviviruses.

Investigation of Sonosensitizers Based on Phenothiazinium Photosensitizers

The main advantage of sonodynamic therapy (SDT), the combining of ultrasound with a sonosensitizer, over photodynamic therapy (PDT) is that ultrasound penetrates deeper into tissues to activate the sonosensitizer, which offers noninvasive therapy for tumors in a site-oriented approach. In this study, we synthesized two symmetrical phenothiazine derivatives in which the methyl groups of MB (methylene blue) have been replaced by a hexyl and hydroxyethyl chains, named 3,7-bis(dihexylamino)-phenothiazin-5-ium iodide (MB6C) and 3,7-bis(di(2-hydroxyethyl)amino)-phenothiazin-5-ium iodide (MBOH), respectively. We explore the efficiency differences between PDT and SDT induced by these phenothiazine derivatives based on the standard of methylene blue (MB). Spectral studies indicate that these MB analogs exhibit sonosensitization ability with a similar tendency to the photosensitization ability. This means that MB, MBOH, and MB6C can be potential photosensitizers and sonosensitizers. After biological evaluation, we conclude that compound MB6C is a potential PDT and SDT candidate because it exhibits higher uptake, efficient intracellular phototoxicity and sonotoxicity over MB and MBOH, with IC50 values of ~2.5 µM and ~5 µM, respectively.

Preparation of blue and green fluorescent dyes based on thioxanthone and phenothiazine derivatives and their thermal-stability, quantum yield properties

Eight dyes were synthesized to connect carbazole or naphthalimidinyl groups with a thioxanthone central ring utilizing an acetylene bond. In this series of fluorescent dyes, a nitrogen atom of both carbazole and naphthalimidyl rings were substituted by an n-butyl or phenyl group to use as a dye intermediate, then coupled to the central ring in the final step. Eight dyes prepared were identified using by 1H NMR, GC-Mass and elemental analyses. Main properties, such as the absorption maxima, emission maxima, molar extinction coefficient and thermal stabilities by TGA analysis of the fluorescent dyes prepared were examined. To optimize the structure of the dye molecules, calculations using a Density Functional Theory (DFT) and Time-Dependent DFT were performed for some dyes. In terms of absorption and emission maxima, six dyes from this series exhibited blue fluorescent emission those in the range of 443–457 nm, whereas two dyes substituted by either N-n-butyl-naphthalimide, or N-phenyl-naphthalimide group were red-shifted comparing to those of six dyes providing a green emission of 520 nm or 525 nm. The quantum yields for six dyes substituted by either N-n-Butyl-carbazole or N-phenyl-carbazole group were higher than those of analogous two dyes containing a naphthalimde group where all of six dyes exhibited 0.81–0.87 these were efficient compared to previous research.

Antioxidant Properties of New Phenothiazine Derivatives.

Phenothiazine and its derivatives have a number of properties that contribute to their wider practical use in the production of biologically active substances, drugs, dyes, etc. Therefore, the synthesis and study of new compounds is of great relevance. The aim of this work was to investigate the antioxidant activity of a number of new phenothiazine derivatives. The patterns of electroreduction of oxygen and its radicals in the presence of phenothiazine derivatives in aqueous ethanol media were studied by voltammetry. The influence of various factors on antioxidant activity was considered by the methods of experiment planning. The optimal conditions for the manifestation of the antioxidant activity of phenothiazine derivatives have been found, which seems to be relevant since it opens up new possibilities for their further use as complex preparations with antioxidant activity, including in psychiatric practice.

Aggregation-Induced Emission in Phenothiazine-Based Fluorophores: An Insight into the Excited State and Aggregate Formation Mechanism

In this study, we report evidence for emissive aggregates of push–pull phenothiazine and phenothiazine dioxide derivatives produced both in water dispersions and in the solid state, highly promising for applications in both biology and material science. An insightful investigation of the aggregation-induced emission (AIE) mechanism was carried out via time-resolved spectroscopies, with nanosecond and femtosecond temporal resolution, coupled with advanced data analysis. Our steady-state and time-resolved spectroscopic results unambiguously show that a significant AIE behavior is activated by the restriction of intramolecular rotations for the phenothiazine derivatives. Investigation of the nonlinear optical properties also revealed that aggregates exhibit notable emission upon two-photon excitation. In particular, the phenothiazine dioxide-based aggregates exhibit remarkable fluorescence efficiencies and large two-photon absorption cross sections, as well as the capability to be internalized in HeLa cells exerting no cytotoxic effect. These aggregate species thus prove to be promising as novel fluorophores for bioimaging.

Synthesis and Characterization of Electroactive PEDOT Platform with N-Octylphenotiazine Derivative

Abstract Poly(3,4-ethylenedioxythiophene) (PEDOT) was synthesized in the presence of a phenothiazine derivative (PTZN_C8). The aim of the research was to use phenothiazine (PTZ) as a doping ion, investigate the possibility of synthesis, and determine the influence of PTZN_C8 on the state of order of forming PEDOT chains. The synthesis of PEDOT in the presence of a PTZN_C8 by cyclic voltammetry allowed characterizing the polymer films by determining the accumulated charge capacity. Different synthetic protocols were used to obtain layers of PEDOT as a matrix and PTZ derivative as a substance that changed the structure of a material. Layers were investigated by Fourier Transform Infrared Spectroscopy (FTIR) to identify the presence of compounds incorporated during synthesis as well as to estimate the degree of polymerization calculated to characterize the length of chains. Ultraviolet-visible spectrophotometry (UV-Vis) spectra allowed drawing releasing curves of PTZN_C8 from the PEDOT matrix. Results showed that it is possible to synthesize PEDOT with PTZN_C8, but deposited PEDOT was modified in terms of the length of the chains—as the content of the PTZN_C8 was higher, the chains were shorter.

Potential of phenothiazines to synergistically block calmodulin and reactivate PP2A in cancer cells.

Phenothiazines (PTZ) were developed as inhibitors of monoamine neurotransmitter receptors, notably dopamine receptors. Because of this activity they have been used for decades as antipsychotic drugs. In addition, they possess significant anti-cancer properties and several attempts for their repurposing were made. However, their incompletely understood polypharmacology is challenging. Here we examined the potential of the PTZ fluphenazine (Flu) and its mustard derivative (Flu-M) to synergistically act on two cancer associated targets, calmodulin (CaM) and the tumor suppressor protein phosphatase 2A (PP2A). Both proteins are known to modulate the Ras- and MAPK-pathway, cell viability and features of cancer cell stemness. Consistently, we show that the combination of a CaM inhibitor and the PP2A activator DT-061 synergistically inhibited the 3D-spheroid formation of MDA-MB-231 (K-Ras-G13D), NCI-H358 (K-Ras-G12C) and A375 (B-raf-V600E) cancer cells, and increased apoptosis in MDA-MB-231. We reasoned that these activities remain combined in PTZ, which were the starting point for PP2A activator development, while several PTZ are known CaM inhibitors. We show that both Flu and Flu-M retained CaM inhibitory activity in vitro and in cells, with a higher potency of the mustard derivative in cells. In line with the CaM dependence of Ras plasma membrane organization, the mustard derivative potently reduced the functional membrane organization of oncogenic Ras, while DT-061 had a negligible effect. Like DT-061, both PTZ potently decreased c-MYC levels, a hallmark of PP2A activation. Benchmarking against the KRAS-G12C specific inhibitor AMG-510 in MIA PaCa-2 cells revealed a higher potency of Flu-M than combinations of DT-061 and a CaM inhibitor on MAPK-output and a strong effect on cell proliferation. While our study is limited, our results suggest that improved PTZ derivatives that retain both, their CaM inhibitory and PP2A activating properties, but have lost their neurological side-effects, may be interesting to pursue further as anti-cancer agents.

A comparative study of the effect of phenothiazine derivatives and their S-oxides on cholinesterase investigated by a new kinetic spectrophotometric method

Aim. To develop a new kinetic spectrophotometric method for determining acetylcholinesterase (AChE) inhibitors – phenothiazine antipsychotic drugs (PhT) and their sulfoxide metabolites (S-oxides) without adding an exogenous catalyst to obtain a chromogenic agent.Materials and methods. The bases of S-oxides of promethazine (PMZ), chlorpromazine (CPM) and thioridazine (THZ) were obtained by oxidizing the corresponding PhT hydrochlorides with diperoxyadipic acid. The structure of the S-oxides of the corresponding PhT synthesized was proven by melting points, spectral characteristics (1H NMR and IR methods) and oscillopolarography results. 1H NMR spectra were recorded on a Varian XL-200 spectrometer. IR spectra were recorded within the range of 4000-400 cm–1 on a SPECORD M-80 spectrometer (Zeiss, Jena, Germany). To register polarograms, a “PO 03 CLA” oscillopolarograph with a three-electrode cell was used. The purity of S-oxides was determined by the high-performance liquid chromatography method on a Zorbax SB, C-18 (250 × 4.6) mm column. Measurements of absorbance of solutions were performed in a 1 cm cuvette on an Evolution 60S UV-Visible Thermo-Scientific Spectrophotometer (USA) (λ = 358 nm).Results and discussion. Acetylcholine (ACh) was found to mimic the activity of peroxidase; based on it, a spectrophotometric system containing ACh–H2O2–p-Ph for a sensitive and selective assessment of the AChE activity and determination of its inhibitors was developed. According to the plots of inhibition efficiency vs inhibitors concentration, the inhibiting ability of chlorpromazine, promethazine and thioridazine and their S-oxides was determined. The IC50 values of CPM, PMZ and THZ and their metabolites in relation to the AChE activity were estimated as 11 ng mL−1 (CPM) and 1.8 ng mL−1 (CPM S-oxide), 17 ng mL−1 (PMZ) and 2.5 ng mL−1 (PMZ S-oxide) and 27 ng mL−1 (THZ 2S,5S-dioxide). The results obtained indicate that S-oxides of the corresponding PhT are selective and potent inhibitors of AChE. The values of the inhibition efficiency obtained for S-oxides of PhT derivatives were an order of magnitude lower than those of the corresponding PhT derivatives.Conclusions. The spectrophotometric method proposed without the addition of other exogenous catalysts holds promise for the on-site determination of PhT antipsychotics and can be additionally used for sensory applications in areas related to environmental protection and food safety, as well as in the chemical-toxicological analysis.

New D−π–D−π–A Systems Based on Phenothiazine Derivatives with Imidazole Structures for Photovoltaics

Two new compounds with an N-octyl phenothiazine core substituted at C(7) position via a triple bond with imidazole-containing butyl or dodecyl chains bearing on the opposite side at the C(7) cyanoacrylate moiety were synthesized. Photophysical and electrochemical studies were performed to evaluate the possibility of applying them in the dye-sensitized solar cells (DSSCs). The investigations were supported by density functional theory and time-dependent DFT. The synthesized dyes showed a similar absorption profile ranging from 250 to 600 nm in solvents and a high value of light-harvesting efficiency of about 0.8. It was found that its photoluminescence quantum yield was solvent-dependent, and the highest value (about 50%) was reached in DMF solution. Electrochemical measurements revealed that both compounds showed electron injection ability from the LUMO of the molecule to the TiO2 conduction band and the possibility of regeneration by an electrolyte. DSSCs sensitized with the phenothiazine derivatives differing in TiO2 thickness and the type of electrolyte (iodide and cobalt) were prepared. Additionally, transient absorption measurements in solution and solar cells were carried out to study excited-state properties and electron transfer dynamics. The influence of the hydrophobic hydrocarbon chain length of the imidazole unit in these dyes as well as TiO2 thickness and the type of electrolyte on the device performance was observed. DSSCs sensitized with phenothiazine with dodecyl chains showed higher photocurrent, open-circuit voltage, and finally the power conversion efficiency, regardless of TiO2 thickness.

A Nanopipette Supported Oil/Water Interface Sensor for the Kinetics Analysis and Determination of Phenothiazine Derivatives

• A nano-ITIES sensor supported by nanopipette for phenothiazine derivative has been proposed. • The transfer Gibbs energies, relative hydrophilicity and the transfer kinetics of promethazine and chlorpromazine has been analyzed. • Determinations for chlorpromazine and promethazine have been performed, excellent stability and satisfactory recoveries in real drug samples have been obtained. • This strategy established a preferable method to evaluate the permeability of drug ions across biomembrane. Phenothiazine is an intermediate in the synthesis of drugs, and its derivatives, i.e., chlorpromazine (CPZ) and promethazine (PMZ), are both the major tranquilizers. Herein, a nanoscale soft sensor constructed utilizing the interface between two immiscible electrolyte solutions (ITIES) for CPZ and PMZ drugs was introduced. A nanopipette with a 60 nm diameter orifice was used to support the ITIES, and voltammetry and amperometry were used for the qualitative and quantitative determination of these two drugs crossing the liquid/liquid (L/L) interface. Half-wave potentials ( Δ w o φ 1 / 2 ) of 0.107 V and 0.092 V (vs. Δ w o φ 1 / 2 , T E A + ) for PMZ + and CPZ + transfer from water to 1,2-dichloroethane (DCE) were obtained, respectively. Subsequently, the kinetics and effective hydrophilicity of these two drugs were thoroughly investigated. Moreover, there were two calibration curves for the determination results between the current and the concentration range for CPZ + and PMZ + by cyclic voltammetry (the concentrations range from 0.1 to 10 mmol −1 ) and amperometry (the concentrations range from 0.02 to 10 mmol −1 ). Finally, the actual drug recovery for these two drugs ranged from 94.83% to 111.02%, which indicates the accuracy in actual medicine is good. The above work provides a soft nano-liquid/liquid interfacial sensor with applications in drugs, including kinetics studies and drug determination, and many applications in detecting pharmaceutical molecules, cellular secretion and other bioorganic compounds.

MO348: Methylene Blue Beneficial Effect in Treatment of Renal Calculi in Patient With Recurrent Urinary Tract Infection

Abstract BACKGROUND AND AIMS Assessment of efficacy of fixed combination of cranberry and sage extract with methylene blue (MBC) in dose of 30 mg twice daily in the prevention and management of chronic renal calculous disease. METHOD In 87 patients who complained recurrent urinary tract infection (UTI)—55 pts with pyelonephritis and 32 with cystitis—at least three episodes in 12 months, the impact of 3 months treatment of MBC with on renal calculi was investigated. All patients were older than 18 years without any biochemical or congenital kidney abnormalities, coagulopathies with size of renal stone over 10 mm. Simultaneous administration of phenothiazine derivatives, SSRI, MAO, tricyclic or any other antidepressants we excluded. A total of 39 (45%) of the patients with a history of nephrolithotomy in the past were included. RESULTS In most cases, patients were supervised during 12 months with 2–3 courses of MBC during the year. A total of 18 pts (21%) have passed no further stones with dramatic improvement of quality of life, and 47 (54%) have improved clinically with reduction of calculi size. A total of 79 pts (91%) reported overall clinical improvement of UTI symptoms and quality of life. The main disadvantage during MBC administration could be discoloration of the urine in light blue or green color. No side or adverse effects were observed during the whole period of the trial. CONCLUSION Methylene blue could be a promising solution in the management of patients with multiple small renal calculi, especially with necessity to reduce the level of concomitant infection without antibiotic and may be useful in the prevention of new stone formation.

Cover Feature: Design of Stimuli‐Responsive Phenothiazine Derivatives with Triplet‐Related Dual Emission and High‐Contrast Mechanochromism Guided by Polymorph Prediction (Chem. Eur. J. 29/2022)

The potential conformations of phenthiazine derivatives have been predicted by Polymorph Prediction. The crystals of those derivatives with the potential to form both quasi-axial and quasi-equatorial conformations can undergo conformation transition and show high-contrast mechanochromism from local emission (LE) to intramolecular or intermolecular charge transfer (CT) emission. All the derivatives also exhibit aggregation-induced emission and triplet-related dual emission characters. More information can be found in the Research Article by S. Xiao, T. Yi, and co-workers (DOI: 10.1002/chem.202200458).

Phenothiazine Derivatives as Potential Antiproliferative Agents: A Mini- Review

Abstract: Research for discovering chemical entities with antiproliferative properties to combat globally rising cancer cases has witnessed tremendous interest in recent years. Phenothiazines possess novel antiproliferative potentials and have often be described as crucial sources of scaffolds for anticancer drug discovery. Some several phenothiazine-hybrid compounds recently synthesised are effective against various cancer cell lines with improved multidrug resistance. In synthesising these phenothiazine-derivatives, therapeutic potentials of the phenothiazines are exploited, and they are enriched by molecular hybridisation with moieties known to possess great pharmacological profiles. This article critically reviews the anticancer properties of phenothiazine derivatives and focuses on the possibility of the derivation of the leads for a further spectrum of antiproliferative activities.

Design of Stimuli-Responsive Phenothiazine Derivatives with Triplet-Related Dual Emission and High-Contrast Mechanochromism Guided by Polymorph Prediction.

The development of high-contrast stimulus-responsive materials with excited triplet emission is of great significance for anti-counterfeiting, sensor and memory applications, but remains a challenge. Here, we report a strategy for the rational design of stimulus-responsive phenothiazine derivatives with triplet-related dual emissions and high-contrast mechanochromism guided by Polymorph Prediction. The designed phenothiazine derivatives have the characters of simple structures, a facile synthetic procedure, and a good crystalline nature. We found that the crystals of those derivatives with the potential to form both quasi-axial (ax) and quasi-equatorial (eq) conformations could undergo conformation transition and show significant emission difference (Δλem >100 nm) under mechanical force. Meanwhile, all these phenothiazine derivatives exhibit aggregation-induced emission and emit room-temperature phosphorescence or thermally activated delayed fluorescence. The significant luminescent change of these materials under different stimuli gives them promise for applications in encryption and anti-counterfeiting.

DFT and MD investigations of the biomolecules of phenothiazine derivatives: interactions with gold and water molecules and investigations in search of effective drug for SARS-CoV-2

Theoretical analyses of two phenothiazine derivatives, 10-[3-(dimethylamino)-2-methylpropyl]phenothiazine-2-carbonitrile (CYM) and 2-[4-[3-(2-chlorophenothiazin-10-yl)propyl]piperazin-1-yl]ethanol (PAZ) are reported using density functional theory (DFT) and molecular dynamics (MD) simulations. Spectroscopic studies, different electronic and chemical parameters are predicted. Red and yellow in electrostatic potential plot is in rings and oxygen atom in PAZ and C≡N and rings in CYM are sensitive to nucleophilic attacks. The blue in hydrogen atoms refer to electrophilic attack in both PAZ and CYM. Stability of the protein–ligand complex formed with these derivatives and angiotensin-converting enzyme 2 (ACE2) was investigated using MD simulation. Radius of gyration of C-alpha atom of 6VW1 displayed the conformational convergence toward a compact structure leading to stable 6VW1–ligand complex which are also in agreement with root mean square fluctuation (RMSF) values. Localized area predicts reactive sites for Au and H2O molecules interaction with these compounds for further practical applications. Charge density is localized on both molecules and also tries to move toward Au–Au dimer and water molecule and such they are expected to contribute to the sensing performance. Communicated by Ramaswamy H. Sarma