2-substituted Derivatives Research Articles

Design, synthesis and anti-HIV evaluation of novel 5-substituted diarylpyrimidine derivatives as potent HIV-1 NNRTIs

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination therapies against HIV-1. As a continuation of our efforts to discover and develop “me-better” drugs of DAPYs, novel diarylpyrimidine derivatives were designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds demonstrated strong inhibition activity against wide-type HIV-1 strain (IIIB) with EC50 values in the range of 2.5 nM ~ 0.93 μM. Among them, compounds IVB-5–4 and IVB-5–8 were the most potent ones which showed anti-HIV-1IIIB activity much superior than that of Nevirapine, comparable to Efavirenz and Etravirine. What’s more, some compounds also showed low nanomole activity against some mutant strains such as K103N and E138K. The selected compound IVB-5–4 was also evaluated for the activity against reverse transcriptase (RT), and exhibited submicromolar IC50 values indicating that this series compounds are specific RT inhibitors. Preliminary structure–activity relationships and modeling studies of these new analogues provide valuable avenues for future molecular optimization.

The Antifungal Activity of HMA, an Amiloride Analog and Inhibitor of Na+/H+ Exchangers.

One path toward identifying effective and easily accessible antifungals is to repurpose commonly used drugs. Amiloride, a widely used diuretic, inhibits different isoforms of Na+/H+ exchangers, Na+ channels, and Na+/Ca2+ exchangers. Here, we found that amiloride had poor antifungal activity against isolates of Cryptococcus prompting the examination of the amiloride analog, HMA [5-(N,N-hexamethylene)amiloride]. HMA possesses strong activity against Na+/H+ exchangers (NHEs) and little K+-associated toxicity since HMA has only minimal inhibitory effects toward epithelial sodium channels (ENaC), the diuretic and antikaliuretic target of amiloride. Although HMA produced a robust dose-dependent growth inhibition of several fungal isolates, susceptibility assays revealed modest MICs against isolates of Cryptococcus. A checkerboard dilution strategy resulted in fractional inhibitory concentrations (FIC) < 0.5, suggesting that HMA displays synergy with several antifungal azole drugs including posaconazole, voriconazole, and ketoconazole. Itraconazole and ravuconazole showed moderate synergy with HMA across all tested fungal isolates. In combination with HMA, ravuconazole had MICs of 0.004–0.008 μg/ml, a ∼16-fold reduction compared to MICs of ravuconazole when used alone and significantly more effective than the overall MIC90 (0.25 μg/ml) reported for ravuconazole against 541 clinical isolates of Cryptococcus neoformans. In combination with azole drugs, MICs of HMA ranged from 3.2 μM (1 μg/ml) to 26 μM (16 μg/ml), HMA was not cytotoxic at concentrations ≤ 8 μg/ml, but MICs were above the reported HMA Ki of 0.013–2.4 μM for various Na+/H+ exchangers. Our results suggest that HMA has limited potential as a monotherapy and may have additional targets in fungal/yeast cells since strains lacking NHEs remained sensitive to HMA. We determined that the hydrophobic substituent at the 5-amino group of HMA is likely responsible for the observed antifungal activity and synergy with several azoles since derivatives with bulky polar substitutions showed no activity against Cryptococcus, indicating that other 5-substituted HMA derivatives could possess stronger antifungal activity. Moreover, substitution of other positions around the pyrazine core of HMA has not been investigated but could reveal new leads for antifungal drug development.

Invariant and Variable Supramolecular Self-Assembly in 6-Substituted Uracil Derivatives: Insights from X-ray Structures and Quantum Chemical Study

In this study, three new 6-(arylthio)uracil derivatives, namely, 6-(phenylthio)pyrimidine-2,4(1H,3H)-dione (1), C10H8N2O2S; 6-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione (2), C11H10N2O2S; and 6-(3,5-dimethylphenylthio)pyrimidine-2,4(1H,3H)-dione (3), C12H12N2O2S, have been synthesized. Single-crystal structures of these compounds reveal an invariant molecular tape contains alternate R22(8) synthons formed by N–H···O hydrogen bonds in 1 and 3. This alternate hydrogen-bonded pattern disappeared in 2; instead, a new synthon is generated. The lattice energy calculation suggests that the methyl-substituted derivatives (2 and 3) have high stabilization energy than compound 1. The electrostatic potential map reveals the difference in the accepting tendency of the carbonyl oxygen. The Hirshfeld surface and 2D-fingerprint plots analyses demonstrate that the major intermolecular interactions come from H···O contacts in 1, and these contacts were reduced due to the presence of methyl substitutions in 2 and 3. This reduction is compensated by the increase of the same amount of H···H contacts in these structures. Further, the PIXEL energy and DFT calculations at the M06-2X-D3/cc-pVTZ level of theory were used to characterize the dimeric topology formed in structures of 1–3. The intermolecular interaction energies of dimers calculated by the PIXEL method were compared with the B97D3/def2-TZVP level of approximation. Although these molecules’ crystal packing is somewhat different, the energy frameworks show similarities on the respective crystal structure’s shortest axis. Furthermore, the nature and strength of various noncovalent interactions such as N–H···O, C–H···O/S/π, π···π, and a chalcogen bond of type C–S···O═C were evaluated using the Bader’s quantum theory of atoms-in-molecules framework.

In vitro proliferative activity of 6-substituted uracil derivatives

Context: Previously, we investigated the relationship between the nature of the substituent at the 5-position of the uracil ring and the action of the corresponding uracil derivatives on immortalized lung cells. In the present study, we analyzed the impact of some 6-substituted uracil-derivatives on the regeneration potential of the lung cells (LC). Aims: To evaluate uracil derivatives capable of stimulating lung cell proliferation to create drugs that accelerate lung regeneration. Methods: The level of cell proliferation, maximum tolerated dose, and toxic effect of 6-substituted uracil derivatives (9 compounds) were studied on the immortalized lung epithelial cells and compared with the known drug 6-methyluracil. Results: The maximum tolerated dose of compounds for the LC line depends on the chemical structure of the compounds. The highest level of cell proliferation and tolerated was demonstrated when was used 3-methyl-6-cyclopropyluracil and 1-butyl-6-methyluracil. Conclusions: 3-methyl-6-cyclopropyluracil and 1-butyl-6-methyluracil exhibit a high proliferative activity in vitro so they could be recommended for additional studies of regenerative activity in vivo.

Chemoenzymatic Production of Enantiocomplementary 2-Substituted 3-Hydroxycarboxylic Acids from L-α-Amino Acids.

A two-enzyme cascade reaction plus in situ oxidative decarboxylation for the transformation of readily available canonical and non-canonical L-α-amino acids into 2-substituted 3-hydroxy-carboxylic acid derivatives is described. The biocatalytic cascade consisted of an oxidative deamination of L-α-amino acids by an L-α-amino acid deaminase from Cosenzaea myxofaciens, rendering 2-oxoacid intermediates, with an ensuing aldol addition reaction to formaldehyde, catalyzed by metal-dependent (R)- or (S)-selective carboligases namely 2-oxo-3-deoxy-l-rhamnonate aldolase (YfaU) and ketopantoate hydroxymethyltransferase (KPHMT), respectively, furnishing 3-substituted 4-hydroxy-2-oxoacids. The overall substrate conversion was optimized by balancing biocatalyst loading and amino acid and formaldehyde concentrations, yielding 36–98% aldol adduct formation and 91– 98% ee for each enantiomer. Subsequent in situ follow-up chemistry via hydrogen peroxide-driven oxidative decarboxylation afforded the corresponding 2-substituted 3-hydroxycarboxylic acid derivatives.

Synthesis and Characterization of 3-Substituted Indole Derivatives as Novel Mannich Bases

In this study, ten 3-substituted indole derivatives at the 3rd position of indole nucleus were synthesized via Mannich reaction with microwave assisted synthesis and the conventional reflux heating method. Microwave assisted synthesis is more preferrable than reflux method since the microwave irradiation lead to a higher product yields with better purity and improved energy efficiency with shortened reaction time. The structures of 3-substituted indole derivatives were characterized by FT-IR, elemental analysis, 1H NMR and 13C NMR spectroscopy

A Novel Ivermectin-Derived Compound D4 and Its Antimicrobial/Biofilm Properties against MRSA.

Methicillin-resistant Staphylococcus aureus (MRSA) and its biofilms infection is still a serious threat to global health. It is urgent to develop efficient drugs by repositioning or designing drugs to solve this problem. In this study, the antibacterial/biofilm activity and mechanisms of ivermectin (D) and its 4″-position amino substitution derivative (D4) against MRSA were investigated. The minimum inhibitory concentration (MIC) of D was 20 μg/mL, which is four times higher than D4 (MIC = 5 μg/mL). The mechanism research demonstrated that D4 was more potent than D at destroying bacterial cell wall, permeating cell membrane (6.25–36.0% vs 1.92–6.04%) and binding to MRSA genomic DNA. Moreover, after incubation with 10–40 μg/mL D4 for 24 h, the percentages of biofilm decreased by 21.2–92.9%, which was more effective than D (no significant change at 40 μg/mL). The antibiofilm effect is achieved by regulating the expression of related genes (RSH, relQ, rsbU, sigB, spA, and icaD). Additionally, though the higher hemolysis makes D4 a safety risk for intravenous injection, other administration options could be considered as well. Therefore, all the results have indicated that D4 may be a potential candidate compound for the treatment of MRSA and its biofilm infections.

Synthesis and biological evaluation of novel 8- substituted sampangine derivatives as potent inhibitor of Zn2+-Aβ complex mediated toxicity, oxidative stress and inflammation

A series of 8-substituted sampangine derivatives have been designed, synthesized and tested for their ability to inhibit cholinesterase and penetrate the blood–brain barrier. Their chelating ability toward Zn2+ and other biologically relevant metal ions was also demonstrated by isothermal titration calorimetry. The new derivatives exhibited high acetylcholinesterase inhibitory activity, high blood–brain barrier penetration ability and high chelating selectivity for Zn2+. Moreover, compound 10 with the strongest binding affinity to Zn2+ was selected for further research. Western blotting analysis, transmission electron microscopy, DCFH-DA assay and paralysis experiment indicated that compound 10 suppressed the formation of Zn2+-Aβ complexes, alleviated the Zn2+ induced neurotoxicity and inhibited the production of ROS catalyzed by Zn2+ in Aβ42 transgenic C. elegans. Furthermore, compound 10 also inhibited the expressions of pro-inflammatory cytokines, such as NO, TNF-α, IL-6 and IL-1β, induced by Zn2+ + Aβ1-42 in BV2 microglial cells. In general, this work provided new insights into the design and development of potent metal-chelating agents for Alzheimer’s disease treatment.

Application of sulfonic acid fabricated cobalt ferrite nanoparticles as effective magnetic nanocatalyst for green and facile synthesis of benzimidazoles

This work represents the design and synthesis of efficient sulfonated cobalt ferrite solid acid catalyst. The synthesized solid acid green catalyst was characterized using various techniques viz. FT-IR, powder XRD, SEM, TEM and VSM. The obtained catalyst was used to synthesize biologically significant 2-substituted benzimidazole derivatives by condensation between o-phenylenediamine with various aromatic, aliphatic and heterocyclic aldehydes. High yield (up to 98 %), short reaction time (10−25 min), mild reaction condition, wide functional group tolerance, easy work-up procedure and excellent values of green chemistry metrices such as lower E factor (0.126), high RME value (88.83 %), carbon efficiency (100 %) and high atom economy (AE) value (90.65 %), are some salient features of the present catalytic system. Moreover, the catalyst recovery by simply using an external magnet and catalyst reusability up to 7 times without any significant loss in catalytic efficiency are some additional remarkable features of the current protocol.

Synthesis, characterization and potent antimicrobial and antifungal activity of 2-substituted benzimidazole derivatives

Benzimidazole is the heterocyclic compound formed by the fusion of benzene and imidazole ring. Benzimidazole analogs are of great significance because of their clinical application and biological activity. Benzimidazoles are considered as an optimistic class of bioactive heterocyclic compound that possesses a range of biological activities. We have synthesized five substituted Benzimidazole derivative using on both microwave irradiation and conventional heating method. The newly synthesized compounds are characterized by IR, NMR and Mass spectra analysis. In the present study, we have reported the synthesis, spectral studies and biological evaluation of some benzimidazole derivatives. Benzimidazole play important role in medical field with so many pharmacological activities such as antimicrobial, anti bacterial, etc. The potency of this clinically useful drug in treatment in microbial action and other activities has encouraged the development of some more potent and significant compounds.

Synthesis and evaluation of 2,3,4,9-tetrahydro-1H-carbazole derivatives as selective acetylcholinesterase inhibitors: Potential anti-Alzheimer’s agents

Alzheimer’s disease is an irreversible, progressive brain disorder that slowly destroys memory and cognition skills. Dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in Alzheimer's disease. Hence, our focus is to synthesize cholinesterase inhibitors. A series (22 compounds) of 6- and 9-substituted derivatives of 2,3,4,9-tetrahydro-1H-carbazole have been prepared and in vitro evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition by Ellman’s method. By comparing selectivity with standard drug donepezil, amino derivative 3, methylamino derivative 4 and butyl nitro derivative 17 have been found to be selective AChE inhibitors. Borsche-Drechsel cyclization reaction has been carried out to synthesize 2,3,4,9-tetrahydrocarbazole ring followed by nitration, reduction and derivative synthesis.

Substituent effect on the thermophysical properties and thermal dissociation behaviour of 9-substituted anthracene derivatives.

The chemical structure and location of substituents on anthracene derivatives influence the electron balance of the aromatic system, thus determining the wavelengths at which light is absorbed, which results in the photochemically induced dimerization or monomerization. Here, the thermal dissociation kinetics of 7 photodimers of 9-substituted anthracene derivatives are studied using a combination of spectroscopic and calorimetric techniques in the condensed state and compared to scarce literature data on thermal dissociation of other anthracene derivatives. The length and chemical structure of the substituent chains have a clear impact on the melting temperatures of the anthracene derivatives and corresponding photodimers. The crystallinity of the photodimers and monomers in turn influences the thermal dissociation kinetics. The thermal dissociation behaviour and previously published photochemistry data are related to the electronic effects of the substituents by means of the Hammett parameters. Stronger electron-withdrawing effects result in larger red shifts of the maximum wavelength λmax for the photodimerization of the anthracene derivatives. It is also shown that for the studied substitutions on the 9-position of anthracene, the higher the magnitude of the electronic effect - both electron-donating and electron-withdrawing - the faster the thermal dissociation kinetics and thus the lower the thermal stability. The strong electronic effects of the substituents on the thermal and photochemical reactivity of the anthracene derivatives and their photodimers allow tuning of the thermal or photochemical responsiveness, e.g. for polymer networks.

Short syntheses of 1-substituted dibenzothiophene derivatives.

The 1-substituted dibenzothiophene motif is an unusual substitution pattern that has previously been accessed via a multi-step synthesis. We demonstrate a simple one-pot preparation of 1-lithiodibenzothiophene from commercial materials via a cascade of two benzyne additions and conversion to several derivatives by addition of electrophiles. A chiral amine containing the 1-dibenzothiophene motif was also prepared. This work avoids the use of precious metals or tert-butyllithium and is much shorter and more convenient than existing routes to 1-substituted dibenzothiophenes.

Retraction: Monodisperse Pt NPs@rGO as highly efficient and reusable heterogeneous catalysts for the synthesis of 5-substituted 1H-tetrazole derivatives

Retraction of ‘Monodisperse Pt NPs@rGO as highly efficient and reusable heterogeneous catalysts for the synthesis of 5-substituted 1H-tetrazole derivatives’ by İbrahim Esirden et al., Catal. Sci. Technol., 2015, 5, 4452–4457, DOI: 10.1039/C5CY00864F.

Molecular docking studies of 3-substituted 4-phenylamino coumarin derivatives as chemokine receptor inhibitor

Molecular docking studies of 3-substituted 4-phenylamino coumarin derivatives as chemokine receptor inhibitor

Synthesis, Characterization, Crystal Structure and Quantum Chemical Calculations of 2-oxo-2H-chromen-3-yl Acetate

This paper is focused on a combined experimental and theoretical study of 3-substituted coumarin derivative, the 2-oxo-2H-chromen-3-yl acetate (I). The compound was synthesized by reacting chroman-2,3-dione and acetic anhydride in dried diethyl ether in the presence of dried pyridine and crystallized in the orthorhombic crystal system with Pbca space group. The lattice parameters of the structure are a=14.6770 (1), b=7.1079 (1), c=17.6767 (2) Å, α=β=γ=90° with 8 molecules per unit cell (Z=8). The compound has been characterized structurally by Spectroscopy utilizing ¹H NMR, ¹³C NMR and IR techniques and by crystallography using the X-Ray diffraction (XRD) analysis. In the crystallographic study, the positions of the atoms were determined by direct methods and refined to a final R value of 0.038 for 1768 independent reflections. The stabilization of the structure is provided by intermolecular C-H•••O hydrogen bonds extending along [010] direction. Likewise, the presence and nature of intermolecular contacts are determined by the 3-D molecular Hirshfeld surface and 2-D fingerprint plot analysis which indicate the main contributions to the Hirshfeld surface, 38.7% for O ••• H and 28.7% for H •• H. Moreover, the molecular geometry of (I) was as well minimized utilizing density functional theory (DFT/RB3LYP), the frequency calculations with RB3LYP method, the basic <i>ab initio</i> model i.e the restricted Hartree-Fock (RHF) and the exchange component of Perdew and Wang’s 1991 functional B3PW91 methods with the 6-311⁺⁺G(d, p) basis set in ground state. The derived structural parameters highlight very good correlation with the crystallographic results. Frontier molecular orbitals (HOMO-LUMO), their energy gap, the non-linear optical effects (NLO) and related reactive parameters were also computed to better apprehend the properties of the molecule.

Synthesis and stereoselective catalytic transformations of 3-hydroxyisoindolinones.

This review focuses on the synthesis of 3-hydroxyisoindolinones, and their application as substrates in stereoselective catalytic transformations reported from 2010 to date. These compounds have attracted much attention among synthetic chemists, as they are integral structural parts of a number of natural products and biologically active compounds. The first part of this review covers methods based on electrochemical, photochemical, and thermal reactions for the synthesis of 3-hydroxyisoindolinones. The second part focuses on their employment as substrates in transition metal-catalyzed and organocatalyzed stereoselective transformations for the preparation of chiral 3-substituted isoindolinone derivatives.

Investigation of thiolysis of 4-substituted SBD derivatives and rational design of a GSH-selective fluorescent probe.

In order to evaluate 7-sulfonamide benzoxadiazole (SBD) derivatives for the development of fluorescent probes, herein we investigated the thiolysis reactivity and selectivity of a series of SBD compounds with different atoms (N/O/S/Se) at the 4-position. Both SBD-amine and SBD-ether are stable toward biothiols in buffer (pH 7.4), while SBD-selenoether can react efficiently with biothiols GSH/Hcy, Cys, and H2S to produce SBD-SG/S-Hcy, SBD-NH-Cys, and SBD-SH, respectively, with three different sets of spectral signals. Therefore, the SBD-selenoether compounds should be useful platforms for the differentiation of these biothiols. Though SBD-alkylthioether shows much lower reactivity than SBD-selenoether, SBD-arylthioether is a tunable motif and structural modifications at the aryl moiety enable the rate of thiol-mediated thiolysis to be modified. To this end, an ER-targeted GSH-selective fluorescent probe 7 was rationally designed via thiolysis of SBD-arylthioether. Compared with control probe SBD-Cl, probe 7 exhibits improved GSH selectivity and better biocompatibility. In total, this study highlights that the modification at the 4-position of SBD is an efficient strategy for the development of new fluorescent probes with tunable reactivity and selectivity.

Tricyclo[2.1.0.02,5]pent-3-ylidene: Stereoelectronic Control of Bridge-Flapping within a Nonclassical Nucleophilic Carbene.

Tricyclo[2.1.0.02,5]pent-3-ylidene is a carbene foreseen to rearrange to pyramidane (c-C4H4)C, a highly strained molecule featuring an inverted C atom. Modeling of the carbene, using the (U)MPWB1K/cc-pVTZ//(U)MPWB1K/6-311G(d) theoretical model, indicated a large singlet–triplet energy gap (ΔES–T = −45 kcal/mol), a high gas-phase proton affinity (PA = 258 kcal/mol), and a preference for electron-poor alkenes. These properties are consistent with those of nucleophilic carbenes. Structural differences between the Cs-symmetric singlet (ωflap = ±44 deg) and C2v-symmetric triplet (ωflap = 0 deg) stem from nonclassical electron delocalization in the former and the lack thereof in the latter. Degenerate bridge-flapping of the singlet’s main bridge, which comprises the reactive divalent C3 atom, is computed to be slow due to a high activation barrier of the C2v-symmetric transition state (TS) (Ea = 17 kcal/mol). The position of the conformeric equilibrium is subject to stereoelectronic control. 1-Substituted derivatives of the carbene (R ≠ H) are sensitive to σ inductive effects. A proximal conformation is preferred when R is electron-donating and a distal one is favored when R is electron-withdrawing. Finally, carbene rearrangements via 1,2-C atom shift or enyne fragmentation were computed. The C2v-symmetric bridge-flapping TS has the proper geometry to initiate enyne fragmentation.

Benzanthrone dyes as mediators of cascade energy transfer in insulin amyloid fibrils

Amyloid fibrils, a specific type of protein aggregates, involved in the development of a number of human disorders, currently attract a growing interest in biomedical and nanotechnological aspects. Recently, we demonstrated that amyloid assemblies may serve as a molecular framework for the multi-step Förster resonance energy transfer (msFRET) in the system containing the classical amyloid marker Thioflavin T (ThT) as the primary donor, the phosphonium mediator dye TDV, and the squaraine dye SQ1 as the terminal acceptor. In the present study we extended our efforts towards evaluating the possibility of using novel benzanthrone dyes as mediators of msFRET in the insulin amyloid fibrils. The four-chromophore systems: ThT → the 3-substituted benzanthrone derivative (BA) → the squaraine SQ4 → the squaraine SQ1 were designed to select the most effective mediators among a series of benzanthrones including the 3-methoxybenzanthrone (MBA) and its amino- (ABM, A6, A8) and amidino- (AM1, AM2) derivatives. The FRET efficiencies and the enhancement of SQ1 fluorescence in the fibrillar and non-aggregated insulin were compared to assess the suitability of the employed cascade system for amyloid fibril detection. The possible fibril binding sites for the examined dyes were defined based on the molecular docking studies. It is assumed that amyloid-scaffolded multichromophoric systems can be used in nanophotonic devices.