Facile Synthesis of 5-Aryl-N-(pyrazin-2-yl)thiophene-2-carboxamides via Suzuki Cross-Coupling Reactions,Their Electronic and Nonlinear Optical Properties through DFT Calculations

Synthesis of 5-aryl-N-(pyrazin-2-yl)thiophene-2-carboxamides (4a–4n) by a Suzuki cross-coupling reaction of 5-bromo-N-(pyrazin-2-yl)thiophene-2-carboxamide (3) with various aryl/heteroaryl boronic acids/pinacol esters was observed in this article. The intermediate compound 3 was prepared by condensation of pyrazin-2-amine (1) with 5-bromothiophene-2-carboxylic acid (2) mediated by TiCl₄. The target pyrazine analogs (4a–4n) were confirmed by NMR and mass spectrometry. In DFT calculation of target molecules, several reactivity parameters like FMOs (E_HOMO, E_LUMO), HOMO–LUMO energy gap, electron affinity (A), ionization energy (I), electrophilicity index (ω), chemical softness (σ) and chemical hardness (η) were considered and discussed. Effect of various substituents was observed on values of the HOMO–LUMO energy gap and hyperpolarizability. The p-electronic delocalization extended over pyrazine, benzene and thiophene was examined in studying the NLO behavior. The chemical shifts of ¹H NMR of all the synthesized compounds 4a–4n were calculated and compared with the experimental values.     

Antifungal Activity of Chemical Constituents from Piper pesaresanum C. DC. and Derivatives against Phytopathogen Fungi of Cocoa

In this study, the antifungal potential of chemical constituents from Piper pesaresanum and some synthesized derivatives was determined against three phytopathogenic fungi associated with the cocoa crop. The methodology included the phytochemical study on the aerial part of P. pesaresanum, the synthesis of some derivatives and the evaluation of the antifungal activity against the fungi Moniliophthora roreri, Fusarium solani and Phytophthora sp. The chemical study allowed the isolation of three benzoic acid derivatives (1–3), one dihydrochalcone (4) and a mixture of sterols (5–7). Seven derivatives (8–14) were synthesized from the main constituents, of which compounds 9, 10, 12 and 14 are reported for the first time. Benzoic acid derivatives showed strong antifungal activity against M. roreri, of which 11 (3.0 ± 0.8 µM) was the most active compound with an IC₅₀ lower compared with positive control Mancozeb^® (4.9 ± 0.4 µM). Dihydrochalcones and acid derivatives were active against F. solani and Phytophthora sp., of which 3 (32.5 ± 3.3 µM) and 4 (26.7 ± 5.3 µM) were the most active compounds, respectively. The preliminary structure–activity relationship allowed us to establish that prenylated chains and the carboxyl group are important in the antifungal activity of benzoic acid derivatives. Likewise, a positive influence of the carbonyl group on the antifungal activity for dihydrochalcones was deduced.     

Inositol Derivatives with Anti-Inflammatory Activity from Leaves of Solanum capsicoides Allioni

Eight new inositol derivatives, solsurinositols A–H (1–8), were isolated from the 70% EtOH extract of the leaves of Solanum capsicoides Allioni. Careful isolation by silica gel column chromatography followed by preparative high-performance liquid chromatography (HPLC) allowed us to obtain analytically pure compounds 1–8. They shared the same relative stereochemistry on the ring but have different acyl groups attached to various hydroxyl groups. This was the first time that inositol derivatives have been isolated from this plant. The chemical structures of compounds 1–8 were characterized by extensive 1D nuclear magnetic resonance (NMR) and 2D NMR and mass analyses. Meanwhile, the in vitro anti-inflammatory activity of all compounds was determined using lipopolysaccharide (LPS)-induced BV2 microglia, and among the isolates, compounds 5 (IC₅₀ = 11.21 ± 0.14 µM) and 7 (IC₅₀ = 14.5 ± 1.22 µM) were shown to have potential anti-inflammatory activity.     

Antibacterial Thiopeptide GE2270-Congeners from Nonomuraea jiangxiensis

Thiopeptides are macrocyclic natural products with potent bioactivity. Nine new natural thiopeptides (1–9) were obtained from a Nonomuraea jiangxiensis isolated from a terrestrial soil sample collected in Singapore. Even though some of these compounds were previously synthesized or isolated from engineered strains, herein we report the unprecedented isolation of these thiopeptides from a native Nonomuraea jiangxiensis. A comparison with the literature and a detailed analysis of the NMR and HRMS of compounds 1–9 was conducted to assign their chemical structures. The structures of all new compounds were highly related to the thiopeptide antibiotics GE2270, with variations in the substituents on the thiazole and amino acid moieties. Thiopeptides 1–9 exhibited a potent antimicrobial activity against the Gram-positive bacteria, Staphylococcus aureus with MIC₉₀ values ranging from 2 µM to 11 µM. In addition, all compounds were investigated for their cytotoxicity against the human cancer cell line A549, none of the compounds were cytotoxic.     

Preparation,structure elucidation,and antioxidant activity of new bis(thiosemicarbazone) derivatives

Schiff-base–bearing new bis(thiosemicarbazone) derivatives were prepared from terephthalaldehyde and various thiosemicarbazides. FT–IR, ¹H NMR, ¹³C NMR, and UV–Vis spectroscopic methods and elemental analysis were used to elucidate the identification of the synthesized molecules. The in vitro antioxidant activity of the synthesized compounds was analysed with the 1,1-diphenyl-2-picryl hydrazyl free-radical–trapping process. The synthesized compounds exhibited lower antioxidant activity than the standard ascorbic acid. IC₅₀ values of the synthesized molecules measured from 3.81 ± 0.01 to 29.05 ± 0.11 μM. Among the synthesized compounds, compound 3 had the best antioxidant activity. Moreover, this study explained the structure–activity relationship of the synthesized molecules with different substituents in radical trapping reactions.     

Novel Sterically Crowded and Conformationally Constrained α-Aminophosphonates with a Near-Neutral pKa as Highly Accurate 31P NMR pH Probes. Application to Subtle pH Gradients Determination in Dictyostelium discoideum Cells

In order to discover new ³¹P NMR markers for probing subtle pH changes (<0.2 pH unit) in biological environments, fifteen new conformationally constrained or sterically hindered α-aminophosphonates derived from diethyl(2-methylpyrrolidin-2-yl)phosphonate were synthesized and tested for their pH reporting and cytotoxic properties in vitro. All compounds showed near-neutral pK_as (ranging 6.28–6.97), chemical shifts not overlapping those of phosphorus metabolites, and spectroscopic sensitivities (i.e., chemical shifts variation Δδ_ab between the acidic and basic forms) ranging from 9.2–10.7 ppm, being fourfold larger than conventional endogenous markers such as inorganic phosphate. X-ray crystallographic studies combined with predictive empirical relationships and ab initio calculations addressed the inductive and stereochemical effects of substituents linked to the protonated amine function. Satisfactory correlations were established between pK_as and both the 2D structure and pyramidalization at phosphorus, showing that steric crowding around the phosphorus is crucial for modulating Δδ_ab. Finally, the hit ³¹P NMR pH probe 1b bearing an unsubstituted 1,3,2-dioxaphosphorinane ring, which is moderately lipophilic, nontoxic on A549 and NHLF cells, and showing pK_a = 6.45 with Δδ_ab = 10.64 ppm, allowed the first clear-cut evidence of trans-sarcolemmal pH gradients in normoxic Dictyostelium discoideum cells with an accuracy of <0.05 pH units.     

Novel Pyridothienopyrimidine Derivatives: Design,Synthesis and Biological Evaluation as Antimicrobial and Anticancer Agents

The growing risk of antimicrobial resistance besides the continuous increase in the number of cancer patients represents a great threat to global health, which requires intensified efforts to discover new bioactive compounds to use as antimicrobial and anticancer agents. Thus, a new set of pyridothienopyrimidine derivatives 2a,b–9a,b was synthesized via cyclization reactions of 3-amino-thieno[2,3-b]pyridine-2-carboxamides 1a,b with different reagents. All new compounds were evaluated against five bacterial and five fungal strains. Many of the target compounds showed significant antimicrobial activity. In addition, the new derivatives were further subjected to cytotoxicity evaluation against HepG-2 and MCF-7 cancer cell lines. The most potent cytotoxic candidates (3a, 4a, 5a, 6b, 8b and 9b) were examined as EGFR kinase inhibitors. Molecular docking study was also performed to explore the binding modes of these derivatives at the active site of EGFR-PK. Compounds 3a, 5a and 9b displayed broad spectrum antimicrobial activity with MIC ranges of 4–16 µg/mL and potent cytotoxic activity with IC₅₀ ranges of 1.17–2.79 µM. In addition, they provided suppressing activity against EGFR with IC₅₀ ranges of 7.27–17.29 nM, higher than that of erlotinib, IC₅₀ = 27.01 nM.     

Design,Synthesis and Biological Assessment of Rhodanine-Linked Benzenesulfonamide Derivatives as Selective and Potent Human Carbonic Anhydrase Inhibitors

A novel series of twenty-five rhodamine-linked benzenesulfonamide derivatives (7a–u and 9a–d) were synthesized and screened for their inhibitory action against four physiologically relevant human (h) carbonic anhydrase (CA) isoforms, namely hCA I, hCA II, hCA IX, and hCA XII. All the synthesized molecules showed good to excellent inhibition against all the tested isoforms in the nanomolar range due to the presence of the sulfonamide as a zinc binding group. The target compounds were developed from indol-3-ylchalcone-linked benzenesulfonamide where the indol-3-ylchalcone moiety was replaced with rhodanine-linked aldehydes or isatins to improve the inhibition. Interestingly, the molecules were slightly more selective towards hCA IX and XII compared to hCA I and II. The most potent and efficient ones against hCA I were 7h (K_I 22.4 nM) and 9d (K_I 35.8 nM) compared to the standard drug AAZ (K_I 250.0 nM), whereas in case of hCA II inhibition, the derivatives containing the isatin nucleus as a tail were preferred. Collectively, all compounds were endowed with better inhibition against hCA IX compared to AAZ (K_I 25.8 nM) as well as strong potency against hCA XII. Finally, these newly synthesized molecules could be taken as potential leads for the development of isoform selective hCA IX and XII inhibitors.     

Novel BODIPY-bridged cyclotriphosphazenes

Three new 2-component unsubstituted ( 4P ), diiodo- ( 5P ), and dibromo- ( 6P ) distyryl-BODIPY-bridged cyclotriphosphazene dimers were designed and synthesized. The newly synthesized BODIPY-cyclotriphosphazene systems were characterized by ¹ H, ¹³ C, and ³¹ P NMR spectroscopy. The photophysical properties of the distryl-BODIPYs (4–6) and BODIPY-cyclotriphosphazene dyads ( 4P – 6P ) were studied by UV-Vis absorption and fluorescence emission spectroscopy. In these derivatives, the bino-type cyclotriphosphazene derivative bearing unsubstituted BODIPY unit 4P exhibited high fluorescence and no singlet oxygen generation due to the lack of spin converter. The attachment of heavy atoms (iodine and bromine) enabled the production of singlet oxygen. The bino-type BODIPY-cyclotriphosphazenes ( 5P and 6P ) were also used as triplet photosensitizers in the photooxidation of 1,3-diphenylisobenzofuran to endoperoxide via generation of the singlet oxygen in dichloromethane. The singlet oxygen production of these compounds was also investigated via a direct method and produced a singlet oxygen phosphorescence peak at 1270 nm.     

Soyauxinine,a New Indolopyridoquinazoline Alkaloid from the Stem Bark of Araliopsis soyauxii Engl. (Rutaceae)

The chemical investigation of the total alkaloid extract (TAE) of the stem bark of Araliopsis soyauxii (Rutaceae) afforded an unreported indolopyridoquinazoline (compound 1) along with nine previously known alkaloids 2–10. In addition, six semi-synthetic derivatives 3a–c, 4b, 5a and 6a were prepared by allylation and acetonidation of soyauxinium nitrate (5), edulinine (3), ribalinine (4) and arborinine (6). The structures and spectroscopic data of five of them are reported herein for the first time. The suggested mechanism for the formation of the new N-allylindolopyridoquinazoline 5a is presented. The structures of natural and derived compounds were determined employing extensive NMR and MS techniques. The absolute configuration of stereogenic centers in compounds 2–4 were determined using NOESY technique and confirmed by the single-crystal X-ray diffraction (SC-XRD) technique. The use of SC-XRD further enabled us to carry out a structural revision of soyauxinium chloride recently isolated from the same plant to soyauxinium nitrate (5). The TAE, fractions, compounds 1–7 and 9, and semi-synthetic derivatives 3a–c, 4b, 5a and 6a were evaluated for their cytotoxic activity towards the cervix carcinoma cell line KB-3-1. No significant activity was recorded for most of the compounds except for 9, which showed moderate activity against the tested cancer cell lines.     

Reactions of 3-Hydroxy-2-phenyl-1H-benzo[e]isoindol-1-one: A Route to 3-Hydroxy-/3-anilinobenzo[e]indan-1-ones and Benzo[f]phthalazin-1(2H)-ones

New hydroxy- and anilinoindanone derivatives 3 and 4 were synthesized starting from 3-hydroxybenzo[e]isoindolinone 1 via the addition of alkyllithium (s-BuLi, n-BuLi, MeLi or i-PrLi) to the carbonyl group, followed by lactam ring opening and, finally, an intramolecular cyclization leading to target compounds. The same starting material was used for the preparation of the new benzo[f]phthalazinone derivatives 12–16 through multi-step reactions. The target derivative 16 was obtained from the corresponding bromolactam 15 by the Buchwald–Hartwig amination. Structures of the obtained compounds were confirmed by the NMR spectra.     

Design,Synthesis, Crystal Structure,In Vitro and In Silico Evaluation of New N′-Benzylidene-4-tert-butylbenzohydrazide Derivatives as Potent Urease Inhibitors

Background: Hydrazides play a vital role in making biologically active compounds in various fields of chemistry. These determine antioxidant, antidepressant, antimalarial, anti-inflammatory, antiglycating, and antimicrobial activity. In the present study, twenty-three new N′ benzylidene-4-(tert-butyl)benzohydrazide derivatives (4–26) were synthesized by the condensation of aromatic aldehydes and commercially available 4-(tert-butyl)benzoic acid. All the target compounds were successfully synthesized from good to excellent yield; all synthesized derivatives were characterized via spectroscopic techniques such as HREI-MS and ¹H-NMR. Synthesized compounds were evaluated for in vitro urease inhibition. All synthesized derivatives demonstrated good inhibitory activities in the range of IC₅₀ = 13.33 ± 0.58–251.74 ± 6.82 µM as compared with standard thiourea having IC₅₀ = 21.14 ± 0.425 µM. Two compounds, 6 and 25, were found to be more active than standard. SAR revealed that electron donating groups in phenyl ring have more influence on enzyme inhibition. However, to gain insight into the participation of different substituents in synthesized derivatives on the binding interactions with urease enzyme, in silico (computer simulation) molecular modeling analysis was carried out.     

Effect of S–Se Bioisosteric Exchange on Affinity and Intrinsic Efficacy of Novel N-acylhydrazone Derivatives at the Adenosine A2A Receptor

In this work, we evaluated the conformational effect promoted by the isosteric exchange of sulfur by selenium in the heteroaromatic ring of new N-acylhydrazone (NAH) derivatives (3–8, 13, 14), analogues of the cardioactive compounds LASSBio-294 (1) and LASSBio-785 (2). NMR spectra analysis demonstrated a chemical shift variation of the iminic Csp² of NAH S/Se-isosters, suggesting a stronger intramolecular chalcogen interaction for Se-derivatives. To investigate the pharmacological profile of these compounds at the adenosine A_2A receptor (A_2AR), we performed a previously validated functional binding assay. As expected for bioisosteres, the isosteric-S/Se replacement affected neither the affinity nor the intrinsic efficacy of our NAH derivatives (1–8). However, the N-methylated compounds (2, 6–8) presented a weak partial agonist profile at A_2AR, contrary to the non-methylated counterparts (1, 3–5), which appeared as weak inverse agonists. Additionally, retroisosterism between aromatic rings of NAH on S/Se-isosters mimicked the effect of the N-methylation on intrinsic efficacy at A_2AR, while meta-substitution in the phenyl ring of the acyl moiety did not. This study showed that the conformational effect of NAH-N-methylation and aromatic rings retroisosterism changed the intrinsic efficacy on A_2AR, indicating the S/Se-chalcogen effect to drive the conformational behavior of this series of NAH.     

Antimicrobial Triterpenoids and Ingol Diterpenes from Propolis of Semi-Arid Region of Morocco

The chemical composition and antimicrobial activity of propolis from a semi-arid region of Morocco were investigated. Fifteen compounds, including triterpenoids (1, 2, 7–12), macrocyclic diterpenes of ingol type (3–6) and aromatic derivatives (13–15), were isolated by various chromatographic methods. Their structures were elucidated by a combination of spectroscopic and chiroptical methods. Compounds 1 and 3 are new natural compounds, and 2, 4–6, and 9–11 are newly isolated from propolis. Moreover, the full nuclear magnetic resonance (NMR) assignments of three of the known compounds (2, 4 and 5) were reported for the first time. Most of the compounds tested, especially the diterpenes 3, 4, and 6, exhibited very good activity against different strains of bacteria and fungi. Compound 3 showed the strongest activity with minimum inhibitory concentrations (MICs) in the range of 4–64 µg/mL. The combination of isolated triterpenoids and ingol diterpenes was found to be characteristic for Euphorbia spp., and Euphorbia officinarum subsp. echinus could be suggested as a probable and new plant source of propolis.     

Structural Characterization and Assessment of Anti-Inflammatory Activities of Polyphenols and Depsidone Derivatives from Melastoma malabathricum subsp. normale

The roots of Melastoma malabathricum subsp. normale (D. Don) Karst. Mey have been used in traditional ethnic medicine systems in China to treat inflammation-triggered ailments, such as trauma, toothache, and fever. Therefore, the aim of this study is to screen for compounds with anti-inflammatory activity in the title plant. The extract of M. malabathricum subsp. normale roots was separated using various chromatographic methods, such as silica gel, ODS C18, MCI gel, and Sephadex LH-20 column chromatography, as well as semi-preparative HPLC. One new complex tannin, named whiskey tannin D (1), and an undescribed tetracyclic depsidone derivative, named guanxidone B (2), along with nine known polyphenols (2–10) and three known depsidone derivatives (12–14) were obtained from this plant. The structures of all compounds were elucidated by extensive NMR and CD experiments in conjunction with HR-ESI-MS data. All these compounds were isolated from this plant for the first time. Moreover, compounds 1–4, 8, and 10–14 were obtained for the first time from the genus Melastoma, and compounds 1, 2, and 11–14 have not been reported from the family Melastomataceae. This is the first report of complex tannin and depsidone derivatives from M. malabathricum subsp. normale, indicating their chemotaxonomic significance to this plant. Compounds 1–12 were investigated for their anti-inflammatory activities on the production of the nitric oxide (NO) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and compounds 1, 11, and 12 showed anti-inflammatory activities with IC₅₀ values of 6.46 ± 0.23 µM, 8.02 ± 0.35 µM, and 9.82 ± 0.43 µM, respectively. The structure–activity relationship showed that the catechin at glucose C-1 in ellagitannin was the key to its anti-inflammatory activity, while CH₃O- at C-16 of aromatic ring A in depsidone derivatives had little effect on its anti-inflammatory activity. The study of structure–activity relationships is helpful to quickly discover new anti-inflammatory drugs. The successful isolation and structure identification of these compounds, especially complex tannin 1, not only provide materials for the screening of anti-inflammatory compounds, but also provide a basis for the study of chemical taxonomy of the genus Melastoma.     

Synthesis and Cytotoxic Activity Study of Novel 2-(Aryldiazenyl)-3-methyl-1H-benzo[g]indole Derivatives

A novel series of 2-(aryldiazenyl)-3-methyl-1H-benzo[g]indole derivatives (3a–f) were prepared through the cyclization of the corresponding arylamidrazones, employing polyphosphoric acid (PPA) as a cyclizing agent. All of the compounds (3a–f) were characterized using ¹H NMR, ¹³C NMR, MS, elemental analysis, and melting point techniques. The synthesized compounds were evaluated for cytotoxic activity against diverse human cancer cell lines by the National Cancer Institute. While all of the screened compounds were found to be cytotoxic at a 10 µM concentration, two of them (2c) and (3c) were subjected to five dose screens and showed a significant cytotoxicity and selectivity.