Synthesis and antibacterial activity of some new pyrazoles incorporating benzimidazole or indole moiety

Fatigue resistance of photochromic 2,2-diaryl-[2H]-heteroannellated chromenes in solution

Indole diterpenoids (IDTs) are an essential class of structurally diverse fungal secondary metabolites, that generally appear to be restricted to a limited number of fungi, such as Penicillium, Aspergillus, Claviceps, and Epichloe species, etc. These compounds share a typical core structure consisting of a cyclic diterpene skeleton of geranylgeranyl diphosphate (GGPP) and an indole ring moiety derived from indole-3-glycerol phosphate (IGP). 3-geranylgeranylindole (3-GGI) is the common precursor of all IDTs. On this basis, it is modified by cyclization, oxidation, and prenylation to generate a large class of compounds with complex structures. These compounds exhibit antibacterial, anti-insect, and ion channel inhibitory activities. We summarized 204 compounds of IDTs discovered from various fungi over the past 50 years, these compounds were reclassified, and their biological activities were summarized. This review will help to understand the structural diversity of IDTs and provide help for their physiological activities.Graphical

A new Schiff base of 5-chloro-3-phenyl-1H-indole-2-carboxyhydrazide and 3-formyl-2-hydroxy-1H-quinoline (HL), and its Cu(II), Co(II), Ni(II), Zn(II), Cd(II), and Hg(II) complexes have been synthesized and characterized in the light of microanalytical, IR, H1 NMR, UV-Vis, FAB-mass, ESR, XRD, and TGA spectral studies. The magnetic susceptibility measurements and low conductivity data provide evidence for monomeric and neutral nature of the complexes. On the basis of spectral studies and analytical data, it is evident that the Schiff base acts as tridentate ligand. The Cu(II), Co(II), and Ni(II) complexes were octahedral, whereas Zn(II), Cd(II), and Hg(II) complexes were tetrahedral in nature. The redox behavior of the Cu(II) complex was investigated by electrochemical method using cyclic voltammetry. In order to evaluate the effect of metal ions upon chelation, both the ligand and its metal complexes were screened for their antibacterial and antifungal activities by minimum inhibitory concentration (MIC) method. The DNA cleavage experiment performed using agarose gel electrophoresis method showed the cleavage of DNA by all the metal complexes. The free radical scavenging activity of newly synthesized compounds has been determined at a different concentration range by means of their interaction with the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH).

Hybrid derivatives have advantage over the other compounds, because they exhibit the enhanced bioactivity. In this chapter benzothiazole conjugated pyrazole hybrid compounds are taken the study. Pyrazole and benzothiazole scaffolds have their own advantage in the field of medicinal chemistry. In the present study, two series of the pyrazole conjugated benzothiazole derivatives were synthesized by Vilsmeier- Haack reaction, followed by the Schiff’s base formation. The newly synthesized compounds were screened for the in-vitro and in-silico anti-TB activities. They show moderate antibacterial and antioxidant activities. Compounds containing OH, CH3 and Cl groups exhibit the superior antibacterial activity in the series. Majority of the compounds exhibit the excellent in-vitro anti-TB activity, showing the MIC values up to 1.6 μg/mL. Some compounds were show the superior activity compared to the standard (INH and Cfx) and molecular docking studies were also carried out to know the molecular interaction with InhA protein.

Condensation of 2-substituted-3,5-dichloroacetophenones 2a-c obtained from the condensation of 2-hydroxy-3,5-dichloroacetophenone 1 and benzoyl chloride were dissolved in NaOH , on treatment under baker venkatraman transformation in presence of KOH with pyridine gives 1-(2-hydroxy-3,5- dichlorophenyl )-3-substituted-1,3propanedione 3a-c. Then converted into 3–aroyl-6,8-dichloroflavanones 4a-i by using different aromatic aldehyde in the presence of ethanol, Piperidine. The condensation of 4a-i with crystal of iodine in DMF solvent gives 3-aroylflavone 5a-i. The condensation of 5a-i and phenylhydrazinehydrochlorides, piperidine in DMF gives 4-aroyl-3,5diarylpyrazoles 6a-i and condensation of 5a- i and hydroxylaminehydrochlorides gives 4aroyl–3,5diarylisoxazoles 7a –i. The above compounds are screened for their antimicrobial activities and have been found to exhibit significant antibacterial and antifungal activities. The zones of inhibition measured in term of mm.

Pyridine coupled pyrazole analogues as lethal weapon against MRSA: An in-vitro and in-silico approach

The present article reports the development of soft nanohybrids comprising of single walled carbon nanotube (SWCNT) included silver nanoparticles (AgNPs) having superior antibacterial property. In this regard aqueous dispersing agent of carbon nanotube (CNT) containing a silver ion reducing unit was synthesised by the inclusion of tryptophan and tyrosine within the backbone of the amphiphile. The dispersions were characterized spectroscopically and microscopically using TEM, AFM and Raman spectroscopy. The nanotube-nanoparticle conjugates were prepared by the in situ photoreduction of AgNO3. The phenolate residue and the indole moieties of tyrosine and tryptophan, respectively reduces the sliver ion as well as acts as stabilizing agents for the synthesized AgNPs. The nanohybrids were characterized using TEM and AFM. The antibacterial activity of the nanohybrids was studied against Gram-positive (Bacillus subtilis and Micrococcus luteus) and Gram-negative bacteria (Escherichia coli and Klebsiella aerogenes). The SWCNT dispersions showed moderate killing ability (40–60%) against Gram-positive bacteria however no antibacterial activity was observed against the Gram negative ones. Interestingly, the developed SWCNT-amphiphile-AgNP nanohybrids exhibited significant killing ability (∼90%) against all bacteria. Importantly, the cell viability of these newly developed self-assemblies was checked towards chinese hamster ovarian cells and high cell viability was observed after 24 h of incubation. This specific killing of bacterial cells may have been achieved due to the presence of higher –SH containing proteins in the cell walls of the bacteria. The developed nanohybrids were subsequently infused into tissue engineering scaffold agar-gelatin films and the films similarly showed bactericidal activity towards both kinds of bacterial strains while allowing normal growth of eukaryotic cells on the surface of the films.

A general and sustainable approach for the synthesis of benzimidazole-thiazole compounds via an efficient, one-pot, domino, pseudo-four-component reaction using 5-amino-2-mercaptobenzimidazole, aralkyl halides, ammonium thiocyanate, and substituted α-bromo-acetophenones in glacial acetic acid at ambient temperature to give final compounds (4a-p) in good yields in shorter time. The spectral data of synthesized compounds were evaluated by analytical and spectral techniques (IR, 1H-NMR, 13C-NMR, and ESI-HRMS). Further, some of the synthesized compounds were screened for their in-vitro antibacterial activity studies using the agar well diffusion method against Gram-positive Streptococcus pneumoniae (2451) bacteria and Gram-negative Proteous mirabilis (2081) bacteria. Based on the MIC results, it was observed that the most active compounds 4b, 4e, 4f, and 4k show promising antibacterial activity with the zone of inhibition values of 2.85cm 2.75cm, 3.6cm, and 3.3cm against both Gram-negative and positive bacteria cell lines, respectively. Further, we have also insight into the molecular simulation studies, based on the binding results, compound 4i showed stable binding interactions with streptomycin drug with the active site of the gyrase protein (PDB ID: 1KIJ). The structure-activity relationship (SAR) studies of all the title scaffolds were also established. The antibacterial activity, molecular docking studies, and molecular dynamic simulations of the title compounds suggested that these are promising antibacterial active skeletons.

People have been ailing regularly nowadays and conventional antibiotics have become less potent due to drug resistance. The molecular architecture of the antibiotics issued to patients has only marginally changed since their discovery, thus this has caused microorganisms to adapt or survive the repeated administration of the same drugs over time, causing medication to be less effective, and people becoming sicker because the lack of new, different and potent antibiotic structures has enabled bacteria to mutate. This presented the pressing need to develop pyrazole compounds because they suit the category of being structurally different and have been reported to exhibit excellent antibacterial activities. To obtain pyrazole derivatives, Microwave-Assisted Organic Synthesis (MAOS) was utilized to synthesize ten novel compounds of (4Z)-4-arylidene-4,5-dihydro-3-methyl-5-oxopyrazole-1-carbothioamide derivatives (4a-4j) by a one-pot multicomponent reaction (MCR) methodology that is ecofriendly and adhering to green chemistry principles, occurring by catalyst-free in a waterethanol solvent system. The methodology to access novel pyrazoles (4a-4j) in this study is superior to conventional pyrazole synthesis because it requires harsh reaction conditions and expensive catalysts, which deviates from green chemistry. All synthesized compounds (4a-4j) were fully characterized and confirmed by 1H NMR, 13C NMR, 2D NMR, FTIR and TOF-MS. Antimicrobial study was performed against two Gram-negative and two Gram-positive strains viz. Escherichia Coli (E.Coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus Aureus (S. Aureus), and Streptococcus pneumoniae (S. pneumoniae), respectively, and amoxicillin was used as the reference drug. It was found that only 4c and 4j exhibited activity against E. coli and their Minimum Inhibitory Concentration ( MIC) values were 1.38 and 2.50 mg/mL, respectively. In contrast, Amoxicillin displayed a lower MIC value of 0.0306 mg/mL, thereby suggesting that amoxicillin is more effective than the synthesized pyrazoles against E. coli. Pyrazoles 4a, 4d, and 4g showed no antibacterial activity against P. aeruginosa. Compounds 4b, 4c, 4e, 4f, 4h, 4i, and 4j displayed varying MIC values ranging from 0.212 to 0.625 mg/mL against S. aureus, 4i being 0.212 mg/mL the lowest MIC value. Amoxicillin displayed a lower MIC value than all the pyrazoles against P. aeruginosa. Against S. pneumoniae, 4j demonstrated an excellent antibacterial potential with a lower MIC value of 0.0156 mg/mL compared to that of amoxicillin (0.0306 mg/mL). The other pyrazoles displayed marginally higher MIC values than amoxicillin; 4g showed no activity for S. aureus. However, 4i displayed the lowest MIC value, suggesting its potential as an antibacterial agent. It was percieved that the unsubstituted phenyl ring in 4i contributed to its enhanced potency against test bacteria. Molecular docking studies were performed to predict the binding sites and affinities of the pyrazoles, revealing that they primarily target Penicillin Binding Proteins (PBPs) in the test bacteria. Docking scores for E. coli ranged from -6.7 to -7.9 kcal/mol and compound 4f exclusively exhibited the best docking score of -8.1 kcal/mol against E. coli better than amoxicillin’s docked score of -7.0 kcal/mol. Docking scores for P. aeruginosa ranged from - 6.8 to -7.7 kcal/mol. Compounds 4g and 4j displayed the highest negative docking scores of - 7.7 kcal/mol, outperforming amoxicillin thereby suggesting their potential as inhibitors, however 4b and 4f were comparable. Furthermore, in silico simulation, Molecular Dynamics (MD) studies were conducted for 4g and 4j. Docking scores for S. pneumoniae range from - 7.2 to -8.1 kcal/mol. Compound 4j displayed the highest negative docking score. Agreement between docking and in vitro results reinforces 4j as a potential inhibitor. The pyrazoles exhibited docking scores between -5.5 and -6.6 kcal/mol for S. aureus with 4j showing potential as an inhibitor. While lower than other PBPs, some pyrazoles are comparable to amoxicillin. Furthermor, the pyrazoles exhibited LogP (Lipophilicity) values oscillating between 1 and 2.5, indicating better bioavailability. Amoxicillin, partitioned close to an aqueous phase, showed by a negative LogP value of -0.29. Amoxicillin’s LD50 (lethal dose for killing 50% of the bacteria) is 15 g/kg, suggesting non-toxicity orally. Among pyrazoles, only compound 4c shares this safety profile as amoxicillin, qualifying 4c to be an orally administered antibacterial agent. Other pyrazoles fall into toxicity class 4, necessitating alternative administration routes, such as IV (Intravenous) or IM (Intramuscular). All studied compounds showed no affinity for BBB (Blood-Brain Barrier) permeability or P-glycoprotein binding, indicating they can traverse the system without hindrance from nonspecific enzymes or tissues. Compound 4d does not inhibit any CYP (Cytochrome P450) isoenzymes, similar to amoxicillin. Compound 4e selectively inhibits CYP 3A4, relevant for drug metabolism.

Synthesis, Identification, Antibacterial Activity, ADME/T and 1BNA-Docking Investigations of 8-Quinolinol Analogs Bearing a Benzimidazole Moiety

Synthesis of bioactive heterocyclic compounds comprising pyrrolidinone linked to a benzimidazole moiety by an eco-friendly and efficient route was investigated. The targeted scaffolds were synthesized from substituted arylamines and available o-phenylenediamine under ultrasonic irradiation in the presence of a mixture of a deep eutectic solvent (DES) and hierarchical TiO2 (H-TiO2) microspheres as a green catalytic system. Two DESs were synthesized by separately mixing FeCl2 and CuCl2 with urea. On the other hand, hierarchical TiO2 (H-TiO2) was synthesized by a solvothermal route and characterized by XRD, SEM, Raman spectroscopy, and XPS. The results demonstrate that the best reaction yields are obtained by using H-TiO2 microspheres in the DES. Besides, the synthesized compounds were screened for their antibacterial activity against different bacteria. Overall, eight derivatives were confirmed to exhibit antibacterial activity.

Condensation of 4-oxo-3,4,5,6,7,8-hexahydrobenzo [b]thieno [2,3-d]-pyrimidine (I) with allyl bromide or ethyl chloroacetate gave (IIa, b). Interaction of the ester derivative IIb with hydrazine hydrate furnished the hydrazide derivative III which was used as starting material for the synthesis of pyrazoles, oxadiazoles, thiosemicarbazide and hydrazone derivatives IV, V, VI, VII, VIII, IX, and XI respectively. Cyclodehydration of thiosemicarbazide derivative IX with sodium hydroxide resulted in the formation of N-phenyl-mercaptotriazole derivative X. The thiazolidenones (XIIa–d) were obtained through the interaction of the hydrazone derivatives XI with mercaptoacetic acid. The obtained compounds have been characterized on the basis of their spectral (IR, PMR and Mass) data and elemental analysis. Most of these compounds have been found to exhibit good antibacterial and antifungal activities. The stability of some biologically active compounds towards gamma radiation have been investigated.

Benzimidazole and its scaffolds are considered as an important heterocyclic motif containing two annular nitrogen atoms of bicyclic compound fused with benzene to imidazole ring established and obtained in many synthetic and natural compounds. In recent years, a few marketed drugs containing 1,2,5-trisubstituted benzimidazoles have shown extensive interest with anticancer (Bendamustine), antifungal (Benomyl), analgesic (Etonitazine), antihypertensive (Telmisartan) and antihistaminic (Norastemizole) activities etc. It also exhibits varied pharmaceutical applications resembling antibacterial, antifungal, anti-inflammatory, antitumor, anthelminthic, antihypertensive, anti-HIVs, antiulcer, anti-convulsant, and anti-diabetic activities. In addition, most of the drugs have substitution at 2nd and 5th position at the benzimidazole core. Moreover; at these two positions, substitutions of the benzimidazole moiety were recognized as fundamental for potency of receptor binding and receptor activation.

The benzazole nucleus is found in many promising small molecules such as anticancer and antibacterial agents. Bendamustine (Alkylating agent), Nocodazole (Mitotic inhibitor), Veliparib (PARP inhibitor), and Glasdegib (SMO inhibitor) are being clinically used as anticancer therapeutic which bear benzimidazole moiety. Based on the principle of bioisosterism, in the present work, 23 compounds belonging to 2-(3,4-dimethoxyphenyl)benzazoles and imidazopyridine series were synthesized and evaluated for their anticancer and antimicrobial activities. A series of new 2-(3,4-dimethoxyphenyl)-1H-benz(or pyrido)azoles were synthesized and evaluated for their anticancer and antimicrobial activities. N-(5-chloro-2-hdroxyphenyl)-3,4-dimethoxybenzamide 1, was obtained by the amidation of 2-hydroxy-5-chloroaniline with 3,4-dimethoxybenzoic acid by using 1,1'-carbonyldiimidazole. Cyclization of 1 to benzoxazole derivative 2, was achieved by p-toluenesulfonic acid. Other 1H-benz(or pyrido)azoles were prepared by the reaction between 2-aminothiophenol, ophenylenediamine, o-pyridinediamine with sodium metabisulfite adduct of 3,4-dimethoxybenzaldehyde. The NMR assignments of the dimethoxy groups were established by the NOESY spectra. Compound 12, bearing two chlorine atoms at the 5(4) and 7(6) positions of the benzene moiety of benzimidazole was found the most potent analogue against A549 cells with the GI50 value of 1.5 μg/mL. Moreover, 24 showed remarkable cell growth inhibition against MCF-7 and HeLa cells with the GI50 values of 7 and 5.5 μg/mL, respectively. The synthesized compounds have no important antibacterial and antifungal activities. It could be concluded that the introduction of di-chloro atoms at the phenyl ring of 2-(3,4-dimethoxyphenyl)-1H-benzimidazoles increases significant cytotoxicity to selected human tumor cell lines in comparison to other all benzazoles synthesized. Unsubstituted 2-(3,4- dimethoxyphenyl)-imidazopyridines also gave good inhibitory profile against A549 and HeLa cells.

Maculalactones are bioactive γ-butyrolactone natural products with promising antifouling properties, yet their limited availability constrains further development. Here, we report the identification and characterization of the key biosynthetic enzymes MacE and MacF from the maculalactone (mac) biosynthetic gene cluster in Nodularia sp. NIES-3585. In vitro reconstitution confirmed that MacE catalyzes acyloin condensation between phenylpyruvic acids, while MacF mediates subsequent fusion of the MacE product with cinnamoyl-CoA derivatives. Structure-guided engineering improved enzyme solubility, enabling systematic substrate scope expansion. Through a one-pot enzymatic synthesis, we synthesized 13 maculalactone derivatives with yields reaching more than 96%, while a complementary combinatorial biosynthesis approach enabled the incorporation of sterically demanding indole moieties, thereby significantly expanding the maculalactone structural space. Bioactivity screening against A549 lung adenocarcinoma cells revealed moderate cytotoxicity (IC₅₀ = 20.82–56.64 μM), with methylation of phenol groups significantly enhancing activity. Several analogs exhibited notable antibacterial activity against clinically relevant Gram-positive pathogens, including Streptococcus pneumoniae. Our work provides a sustainable platform for producing structurally diverse maculalactones, laying the foundation for future biomedical applications.