Heterocyclic Analogues Research Articles

Differences in sex hormone levels in the menstrual cycle due to tobacco smoking - myth or reality?

Tobacco smoke contains, among others, polycyclic aromatic hydrocarbons (PAHs), heterocyclic analogues, aromatic amines, N-nitrosamines, volatile hydrocarbons, aldehydes, phenols, miscellaneous organic compounds, metals, and inorganic compounds. Tobacco smoking can harm women's reproductive system and may reduce fertility. The objective of the study was to explore the effect of tobacco smoke on the menstrual cycle due to smoking and second-hand smoke-exposure. The study was performed on 153 women of reproductive age, who received care at the Gynaecological-Obstetric Clinical Hospital of the Poznan University of Medical Sciences. They were divided into three treatment groups: non-smokers, secondhand smokers, and smokers. Comprehensive assessment of all hormone levels: follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17β-oestradiol (E2), and progesterone (P), in the various phases of the menstrual cycle and with concomitant determinations of serum cotinine concentrations was performed. The menstrual cycle was observed with ultrasonography. Cigarette smoking may be an important factor in disrupting reproduction: 1. The increase in the oestradiol E2 level was accompanied by significantly lowered serum cotinine concentrations in tobacco smokers; 2. In smoking patients, the serum level of LH significantly increased on the first days of the menstrual cycle; 3. The higher levels of P (in the 14th and 21st days) were assumed to be the result of a longer menstrual cycle. Active and passive smoking may be an important contributor to reproductive health issues and deserves greater focus in health education programs directed towards women of reproductive age.

Nickel-Borolide Complexes and Their Complex Electronic Structure.

Borolides (BC42-) can be considered as dianionic heterocyclic analogues of monoanionic cyclopentadienides. Although both are formally six-π-electron donors, we herein demonstrate that the electronic structure of their corresponding transition metal complexes differs significantly, leading to altered properties. Specifically, the 18-electron sandwich complex Ni(iPr2NBC4Ph2)2 (1) features an ∼90° angle between the Ni-B-N planes and is best described as a combination of three limiting resonance structures with the major contribution stemming from a formally Ni2+ species bound to two monoanionic radical (BC4•-) ligands. Compound 1 displays two sequential one-electron oxidation events over a small potential range of <0.2 V, which strikingly contrasts the large potential separations between redox partners in the family of metallocenes, and the potential reasons for this unusual observation are discussed.

Screening and fluorescence investigation on favipiravir cocrystal

Favipiravir was chosen as a model for study on cocrystal screening of nucleoside analog. Seven coformer candidates were selected according to supramolecular synthon method and verified with molecular modeling and hot-stage. Only 4-amino benzoic acid was able to form cocrystal with the color transformation from white to yellow. Fluorescence study was investigated and compared during cocrystallization. Due to the fluorescent emission nature of nitrogen heterocyclic nucleoside analog, fluorescence could also be utilized as a promising tool in screening cocrystals. This study provides an efficient pathway toward nucleoside analog cocrystal and affords a fluorescent screening method for drug cocrystal research.

Ecological, Physiological and Biochemical Adaptation in Helminth: Trends in Evolution of Anthelminthic Chemical Agents

This paper discusses the landmark anthelminthic substances – traditional medicine components, different categories of pluripotential synthetic and naturally occurring compounds. Much attention is paid to the sections devoted to recent discoveries (Emodepside, Monepantel, Derquantel, Tribendimidine) and to some promising works. This review focused on some aspects of molecular mechanisms of action of anthelminthic substances and of helminth adaptation to anthelminthic substances, and on alternative worming treatment options. A new substance development, be it designing a new compound or identification of properties of any existing compounds, is a time-consuming and expensive process. Application of the diversification (different types of compounds) and the focused (related compounds) screenings, software-based evaluation of anthelminthic activity in silico, chemical and genetic trials on model small animals (nematodes Artemia salina, Caenorhabditis elegans, etc.) are intended to accelerate introduction of new substances. Further knowledge in molecular action mechanisms of anthelminthic agents and in resistance development would improve planning of helminthoses control protocols. Based on the systemic analysis of particular features of the chemical structure of anthelminthic substances, the hypothesis on the viability of the targeted search for such compounds among the derivatives of conditionally progenitor cyclic hydrocarbons – benzene, indene, naphthalene, 1Н-cyclopenth [a]-naphthalene, anthracene and phenanthrene – by alternating absolutely unsaturated and saturated structures, including heterocyclic analogues containing nitrogen, oxygen and sulfur and different substitutes and functional groups, was voiced.

Unravelling the Selectivity of 6,7-Dimethyl Quinoxaline Analogs for Kinase Inhibition: An Insight towards the Development of Alzheimer's Therapeutics.

Untangling the most selective kinase inhibitors via pharmacological intervention remains one of the challenging affairs to date. In accordance to this drift, herein we describe the design and synthesis of a set of new heterocyclic analogs consisting of 6,7-dimethyl Quinoxaline, appended to a connector, employing Schiff base strategy (Compounds I-IX). The compounds were characterized by various spectroscopic techniques and the kinase inhibition assay were performed on few prime members of the CMGC family namely the GSK3β, DYRK1A and CLK1 receptors, respectively, that have been known to be directly involved in hyperphosphorylation of Tau. Interestingly the biological evaluation results revealed that Compounds IV and V, with bromo/chloro functionalities in the aromatic core were advantaged of being highly selective towards the target GSK3β over others. To strengthen our analysis, we adopted molecular modelling studies, where compounds IV/V were redocked in the same grid 4AFJ, as that of the reference ligand, 5-aryl-4-carboxamide-1,3-oxazole. Surprisingly, our investigation underpinned that for both the compounds IV/V, a primary H-bonding existed between the designed molecules (IV/V) and Val 135 residue in the receptor GSK3β, in line with the reference ligand. We attribute this interaction to instigate potency in the compounds. Indeed the other non-covalent interaction, between the derivative's aromatic nucleus and Arg 141/Thr 138 in the receptor GSK3β, might have been responsible for enhancing the selectivity in the targets. Overall, we feel that the present work depicts a logical demonstration towards fine tuning the efficacy of the inhibitors through systematic adjustment of electron density at appropriate positions in the aromatic ring be it the main quinoxaline or the other aromatic nucleus. Thus this pathway offers a convenient strategy for the development of efficient therapeutics for diversified neurodegenerative diseases like that of Alzheimer's.

In-silico Design of a Core Scaffold Pyrazolone Fused Heterocyclic Analogues as Dual Inhibitors Targeting Breast Cancer

In-silico Design of a Core Scaffold Pyrazolone Fused Heterocyclic Analogues as Dual Inhibitors Targeting Breast Cancer

Occurrence and Distribution of Polycyclic Aromatic Hydrocarbons and Nitrogen-Containing Polycyclic Aromatic Hydrocarbon Analogues in Soils from the Niger Delta, Nigeria

Polycyclic aromatic hydrocarbons (PAHs) and the nitrogen heterocyclic analogues (N-PAHs) are known to co-exist in environmental samples. Despite the known toxicity in polluted soils, their distribution remains to be elucidated in specific regions. This study investigated the occurrence and distribution PAHs and N-PAHs in soils from the Niger Delta. Physico-chemical analysis shows that Niger Delta soils are calcic, low in cation-exchange capacity (CEC); with ƩPAHs and ƩN-PAHs ranges of 663.9–1,618,821.2 µg/kg and 488.2–3,510.3 µg/kg, respectively. The most abundant PAHs were 2,6-dimethyl-naphthalene and 4,7-phenanthroline. Petrogenic-PAHs dominated the crude oil spill sites; while, pyrogenic-PAHs were abundant in drilling and gas flaring sites. Oil spill sites recorded elevated levels of N-PAHs, with 3-rings and carcinogenic-N-PAHs showing dominance. Furthermore, ƩPAHs and ƩN-PAHs in the oil rich region exceeded the Alberta and Canadian soil quality guidelines and, are also higher than PAHs/N-PAHs studies in literature. Risk assessment based on Benzo[a]pyrene toxic equivalency (TEQ-B[a]Peq) suggests high ecological risks. This is the first study on the occurrence and distribution of PAHs/N-PAHs in the area, and the data could serve a baseline purpose for risk assessment and remediation of contaminated sites.

Synthesis, characterization, DFT calculation, antifungal, antioxidant, CT-DNA/pBR322 DNA interaction and molecular docking studies of heterocyclic analogs

A series of heterocyclic analogs (2a-2l) was synthesized through condensation of 5-(4-aminophenyl)-1,3,4-oxadiazole-2-thiol and substituted aldehydes in ethanol and characterized by 1H, 13C NMR, IR, UV–visible spectroscopy and mass spectrometry. Optimization of the structure of heterocyclic analogs 2c, 2h and 2j was done by density functional theory (DFT) calculations. In vitro antifungal activity and growth pattern analyses of heterocyclic analogs (2a-2l) were evaluated against the Candida albicans. Results exhibited that analog 2c has significant antifungal potential with MIC value of 200 µg/ml comparable with standard drug fluconazole. In vitro hemolysis assay of the analog 2c showed 7.27% hemolysis at 200 µg/ml concentration indicating its nontoxic nature. The interaction of promising compound 2c with CT-DNA was carried out by UV-visible, fluorescence, Time-Resolved fluorescence spectrophotometry, cyclic voltammetry, circular dichroism and viscosity measurements. The UV-visible spectral analysis signifies the formation of complex between heterocyclic analog 2c and CT-DNA. The binding constant (Kb) and Gibb's free energy (ΔG) for 2c were found to be 6.34 × 105 and -33.1 KJmol−1, respectively. Further from fluorescence spectra, linear Stern–Volmer constant (KSV) for 2c was found to be 1.29 × 105. In silico molecular docking study of analog 2c with PDB: 1BNA confirmed the intercalation mode of binding which were corroborated with in vitro DNA binding results. The interaction study of analog 2c with supercoiled pBR322 plasmid DNA with varying concentration (3–20 mM) was carried out by Agarose gel electrophoresis. Antioxidant activity was also carried out for compounds 2a-2l using DPPH and H2O2 assay.

Photocyclization of Diarylethenes: The Effect of Electron and Proton Acceptors as Additives.

The effect of electron and proton acceptors on the photocyclization of diarylethenes has been studied. Without any additives, the deprotonation reaction is predominant, although other processes, including the sigmatropic shift, are not excluded. A deuterium exchange experiment has shown that a strong base (DABCO) facilitates the deprotonation reaction, thereby limiting the sigmatropic shift. In the presence of an oxidizing agent or additional sources of radicals (O2, I2, TEMPO), the processes of deprotonation and rearrangement (H-shift) are practically not observed, and the reaction proceeds along a radical pathway with the formation of phenanthrene or its heterocyclic analogue.

The inhibitory potency of isoxazole-curcumin analogue for the management of breast cancer: A comparative in vitro and molecular modeling investigation

Curcumin, a potent phytochemical derived from the spice element turmeric, has been identified as a herbal remedy decades ago and has displayed promise in the field of medicinal chemistry. However, multiple traits associated with curcumin, such as poor bioavailability and instability, limit its effectiveness to be accepted as a lead drug-like entity. Different reactive sites in its chemical structure have been identified to incorporate modifications as attempts to improving its efficacy. The diketo group present in the center of the structural scaffold has been touted as the group responsible for the instability of curcumin, and substituting it with a heterocyclic ring contributes to improved stability. In this study, four heterocyclic curcumin analogues, representing some broad groups of heterocyclic curcuminoids (isoxazole-, pyrazole-, N-phenyl pyrazole- and N-amido-pyrazole-based), have been synthesized by a simple one-pot synthesis and have been characterized by FTIR, 1H-NMR, 13C-NMR, DSC and LC–MS. To predict its potential anticancer efficacy, the compounds have been analyzed by computational studies via molecular docking for their regulatory role against three key proteins, namely GSK-3β—of which abnormal regulation and expression is associated with cancer; Bcl-2—an apoptosis regulator; and PR which is a key nuclear receptor involved in breast cancer development. One of the compounds, isoxazole-curcumin, has consistently indicated a better docking score than the other tested compounds as well as curcumin. Apart from docking, the compounds have also been profiled for their ADME properties as well as free energy binding calculations. Further, the in vitro cytotoxic evaluation of the analogues was carried out by SRB assay in breast cancer cell line (MCF7), out of which isoxazole-curcumin (IC50–3.97 µM) has displayed a sevenfold superior activity than curcumin (IC50–21.89 µM). In the collation of results, it can be suggested that isoxazole-curcumin behaves as a potential lead owing to its ability to be involved in a regulatory role with multiple significant cancer proteins and hence deserves further investigations in the development of small molecule-based anti-breast cancer agents.Graphic abstract

One-Step Synthesis of Triphenylphosphonium Salts from (Het)arylmethyl Alcohols.

Two approaches for the synthesis of substituted phosphonium salts from easily available benzyl alcohols and their heterocyclic analogs have been developed. The developed protocols are complementary: the direct mixing of alcohol, trimethylsilyl bromide, and triphenylphosphine in 1,4-dioxane followed by heating at 80 °C was found to be more efficient for acid-sensitive substrates, such as salicyl or furfuryl alcohols as well as secondary benzyl alcohols, while a one-pot procedure including sequential addition of trimethylsilyl bromide and triphenylphosphine gave higher yields for benzyl alcohols bearing electroneutral or electron-withdrawing substituents.

CRYSTALLINE AND HETEROCYCLYC AROMATIC COMPOUNDS IN GEORGIAN PETROLEUM

The individual composition of polycyclic aromatic hydrocarbons has been studied in high boiling (340–590°) fractions of Norio oil (wells 200, 201) which are characterized by high content of aromatic hydrocarbons and high intensity fluorescence. The eluates obtained by adsorption fractionation of aromatic hydrocarbons separated by aniline and concentrates of their crystalline components have been studied by GC, MS and GC-MS methods. For analysis of the obtained data an automated system of mass deconvolution and identification (AMDIS) was used. In the eluates under investigation the following structures were identified: indenes, tetralines, dinaphtilbenzenes, naphthalenes, fluorenes, phenantrenes, antracenes, mono- and polyalkyl derivatives ofnaphtofluorene and phenantrene, and terpeniles. In crystal samples of the eluates the banzantracene, chrizene, their methyl-, dimethyl and trymethylanaloges, phenantrene derivatives, antracenes and pyrenes were identified. The heterocyclic analogues of polycyclic aromatic hydrocarbons likemethylbenzoanthracenes, benzonaphthothiophenes, benzocarbazoles and dibenzthiophene were identified in Georgian oils for the first time.

Synthesis of heterocyclic analogs of isoflavone and homoisoflavone based on 3-formylchromone.

The review is focused on recent developments of chemistry of synthetic analogs of natural compounds, isoflavone and homoisoflavone. The possible synthetic strategies to access heterocyclic analogs of these compounds starting from readily available 3-formylchromone and its derivatives (3-cyanochromone, 2-amino-3-formylchromone) and products of its condensation with simplest C- and N-nucleophiles are discussed. The structural features of the reaction products that depend on the nature of the reaction medium, structure of the starting compounds, and reagent ratio are considered. Particular attention is given to the application of the modern strategies of organic synthesis, namely green chemistry approaches, click reactions, domino reactions, etc. Examples of compounds of this group most promising for clinical application due to wide and pronounced pharmacological effects are given.

A Review an Isatin, Isatin Derivatives and their Pharmacological Activity

Isatin or 1H-indole-2, 3-dione is an indole derivative. Isatin is an important class of heterocyclic compounds. Recently, heterocyclic compounds analogues and their derivatives have attracted strong interest in medicinal chemistry due to their biological and pharmacological properties. The structure have offered a high value of diversity that is proven useful for the development of new medicinal drugs and improved potency,less toxicity and good pharmacological activity. Isatin has a wide varity of pharmacological activities such as an antimicrobial, anticancer, antiviral, anticonvulsant, anti-inflammatory and analgesic etc. The aim of this review is to provide the recent efforts of scinentists in pharmacological screening of isatin, importants and synthesis of isatin derivatives,pharmacological action of isatin and their biological activity.

Respiration Responses of Earthworm to Soil Amended with Phenanthrene and the Nitrogen Heterocyclic Analogues

ABSTRACT A disturbance in the normal physiology of soil macroinvertebrates can cause toxic impacts and/or disruption in mechanisms and rates of respiration. In this work, respiration rates of earthworms exposed to phenanthrene and its nitrogen heterocyclic analogs was investigated over a 30 and 90-d soil-contact-time. The study involved measurement and calculation of CO2 production by earthworms exposed to phenanthrene–N-PAHs amended soils. Data showed that N-PAH chemicals mostly affected the respiration rates of the earthworms compared to the homologous-PAH analog over time. The concentration–time plots showed greater respiration with increase in concentration over time. Calculated respiration inhibition-effect (%) revealed that phenanthrene had low degree of inhibition (27%) in the first 30-d at the highest concentration, while, NPAHs exhibited high degree of inhibitions (>45%) on respiration/physiological function of the exposed earthworms over the 90-d contact-time. Among the N-PAH chemicals, benzo[h]quinoline recorded >25% inhibition even at the lowest concentration (30-d). Statistical analysis of data revealed that N-PAHs maintained strong positive correlation on respiration response of the organisms with increased concentration and time (R2 = 0.803–0.997, p < .05). This suggests that N-PAH chemicals may have caused severe metabolic and physiological stress/inhibitions to soil organisms. Furthermore, the use of earthworm’s respiration rate in polluted soils could likely reshape the understanding of environmental stressors and serve as an early warning indicator for potential ecosystem shifts.

Synthesis, characterization, in vitro biological and computational evaluation of 5-benzyl-4-(benzylideneamino)-2H-1,2,4-triazole-3(4H)-thiones

Triazoles and their heterocyclic analogues are nitrogen-rich versatile pharmacophores easily synthesized and converted to a range of biologically relevant heterocycles. In this context, the present research reports the synthesis, characterization, in vitro antioxidant, cytotoxic and α-glucosidase inhibitory potential of 4-amino-5-benzyl-2H-1,2,4-triazol-3(4H)-thione (3) and 5-benzyl-4-(benzylideneamino)-2H-1,2,4-triazole-3(4H)-thiones 5(a–g). Consequently, the percent DPPH free radical scavenging ability was found to be in the decreasing order of 5 g > 5e > 3 > 5d > 5b > 5c > 5a > 5f. The most potent derivatives (5 g), (5e) and (3) showed significant dose-dependent scavenging ability with IC50 values of 61.22, 74.06 and 94.87 µg/ml, respectively. The antioxidant derivatives were screened in brine shrimp lethality as well as protein kinase inhibitory assay to unveil their toxic nature. The percent mortality was found to be decreasing in the order of 5b > 5f > 3 > 5a > 5 g > 5d > 5e > 5c at 200 µg/ml in brine shrimp lethality assay. Accordingly, three derivatives (5b), (3) and (5f) showed significant percent mortality with LC50 values of 25.88, 32.94 and 34.87 µg/ml, respectively. Similarly, in protein kinase inhibitory assay, maximum inhibitory potential was observed for the derivatives (5 g), (3) and (5e) with MIC values of 50 µg/disc in each case. Likewise, in α-glucosidase inhibition assay, the screened derivatives (3) and (5e) showed notable percent α-glucosidase inhibition (66.78 and 55.15%) with IC50 value of 36.11 µg/ml and 60.33 µg/ml, respectively. Molecular docking studies of the screened derivatives were performed in order to assess their binding potential and mechanism of their binding with α-glucosidase, α-kinase and β-kinase enzymes. Docking simulation revealed that the molecules stabilize themselves inside the active site by establishing non-covalent interactions with critical residues. Noteworthy were the derivatives (3) and (5e) which anchored themselves through various significant electrostatic interactions with the critical residues.

Scholl reaction as a powerful tool for the synthesis of nanographenes: a systematic review.

Nanographenes, or extended polycyclic aromatic hydrocarbons, have been attracting increasing attention owing to their widespread applications in organic electronics. However, the atomically precise fabrication of nanographenes has thus far been achieved only through synthetic organic chemistry. Polycyclic aromatic hydrocarbons (PAHs) are popular research subjects due to their high stability, rigid planar structure, and characteristic optical spectra. The recent discovery of graphene, which can be regarded as giant PAH, has further stimulated research interest in this area. Chemists working with nanographene and heterocyclic analogs thereof have chosen it as their preferred tool for the assembly of large and complex architectures. The Scholl reaction has maintained significant relevance in contemporary organic synthesis with many advances in recent years and now ranks among the most useful C–C bond-forming processes for the generation of the π-conjugated frameworks of nanographene or their heterocyclic analogs. A broad range of oxidants and Lewis acids have found use in Scholl-type processes, including Cu(OTf)2/AlCl3, FeCl3, MoCl5, PIFA/BF3–Et2O, and DDQ, in combination with Brønsted or Lewis acids, and the surface-mediated reaction has found especially wide applications in PAH synthesis. Undoubtedly, the utility of the Scholl reaction is supreme in the construction of nanographene and their heterocyclic analogues. The detailed analysis of the progress achieved in this field reveals that many groups have contributed by pushing the boundary of structural possibilities, expanding into surface-assisted cyclodehydrogenation and developing new reagents. In this review, we highlight and discuss the recent modifications in the Scholl reaction for nanographene synthesis using numerous oxidant systems. In addition, the merits or demerits of each oxidative reagent is described herein.

Heterocyclic Resveratrol Analogs. Synthesis and Physiological Activity: Part 1–Analogs Obtained by the Replacement of Aryl Residues with Heterocyclic Fragments

Resveratrol is a polyphenolic phytoalexin, a stilbene derivative, whose physiological activities have been studied in a large number of studies. It demonstrated antioxidant, antitumor, neuroprotective, anti-inflammatory, antibacterial, and antiviral properties. In the last decade, much attention was paid to the development of resveratrol derivatives with the goal of improving its pharmacological profile and pharmacokinetics. Part 1 of the review is devoted to resveratrol synthetic analogs obtained by the replacement one or two phenyl moieties of the stilbene backbone with bioisosteric heterocyclic fragments. Attention was focused on the methods of synthesis of resveratrol analogs and their biological activity.

Light-driven photoswitching of quinazoline analogues of combretastatin A-4 as an effective approach for targeting skin cancer cells.

A novel quinazoline series of photoswitchable combretastatin A-4 (CA-4) analogues were synthesized and their photochemical properties and antiproliferative activity against A431 epidermoid carcinoma cells were studied. It was found that quinazoline analogues, in contrast to the majority of the known CA-4, exhibit high antiproliferative activity in the E-form as well. Photoswitching of the E-form to the Z-form resulted in a multiple (9-fold) increase in antiproliferative activity. 1H NMR monitoring showed that these compounds are very resistant to UV (λ = 365 nm) or sunlight irradiation and do not undergo photodegradation with a loss of antiproliferative activity that is inherent in heterocyclic analogues of CA-4. Similar photoswitching and an increase in antiproliferative activity are observed on exposure to sunlight. A selected compound (1a-Z51) in sub-micromolar concentrations induced apoptosis in A431 cells, while rad50/ATM/p53 were not involved in cell death. The growth of A431 cells was significantly inhibited after combination treatment with compound 1a-Z51 and chemotherapy drugs (cisplatin or 5-fluorouracil). In summary, the quinazoline analogues of CA-4 represent a promising strategy to achieve a photoswitchable potency for the treatment of cancers, including the development of combination therapies.

A Comprehensive Appraisal of Chalcones and Their Heterocyclic Analogs as Antimicrobial Agents

Owing to the growing demand for compelling antimicrobial agents, chalcones and their heterocyclic derivatives have engrossed prodigious attention of medicinal chemists as an effective clinical template for the synthesis of such agents on account of their structural diversity and molecular flexibility. Chalcones are considered as a fortunate scaffold in the field of both synthetic as well as natural product chemistry. They are reflected as a remarkable section of logically occurring pharmacophores that possess a comprehensive scale of biological activities, such as anti-cancer, anti-malarial, anti-viral and anti-inflammatory, rendering them with a high degree of assortment and noble therapeutic profile. They act as a crucial intermediate for the synthesis of novel heterocyclic skeletons holding biodynamic behavior. This review emphasizes on different aspects of chalcones including their natural sources, recent synthetic methodologies and evaluation of their anti-microbial potential. It is expected as a persuasive compilation on chalcones that may benefit the experts to design potent and less toxic chalcone referents as medicinal agents.