ABSTRACT Chalcones are versatile scaffolds with broad pharmacological relevance, particularly as anti‐inflammatory and anti‐malarial agents. In the current investigation, a series of (3‐arylediene‐1‐phenyl‐1 H ‐pyrazol‐4‐yl)acryloyl‐4‐hydroxy‐6‐methyl‐2 H ‐pyran‐2‐one analogs/1,3‐diarylprop‐2‐en‐1‐ones were successfully synthesized, leveraging dehydroacetic acid (DHA) as the precursor molecule. The choice of DHA is strategic as it is a bioactive and highly versatile scaffold bearing a 4‐hydroxy‐6‐methyl‐2 H ‐pyran‐2‐one moiety, which enhances structural diversity and provides multiple reactive sites for functionalization. Its inherent anti‐microbial, anti‐inflammatory, and anti‐malarial potential offers an added advantage over conventional precursors, thereby increasing the likelihood of generating pharmacologically active chalcone hybrids. The synthetic protocol employed in this study involved the implementation of a Claisen condensation reaction, wherein DHA was reacted with formyl pyrazole to afford the corresponding chalcones, with yields ranging from moderate to good. The synthesized compounds were subjected to a rigorous characterization protocol, involving a battery of analytical techniques, including 1 H‐NMR, 13 C‐NMR, FT‐IR, and HRMS analyses. Biological evaluation focused on anti‐malarial and anti‐inflammatory activities, while molecular docking (PyRx 0.8) was performed to explore binding interactions with cyclooxygenase‐2 (COX‐2; PDB ID: 3LN1) and enoyl‐acyl‐carrier‐protein reductase (EACPR; PDB ID: 1NHG). Notably, compound 3c emerged as the most potent one within the synthesized series, exhibiting remarkable anti‐inflammatory and anti‐malarial potency, as evidenced by its IC 50 values of 7.05 ± 0.17 µM and 0.95 ± 0.06 µM, respectively. Docking studies revealed strong binding affinities and favorable molecular interactions, supporting the observed bioactivities. This study highlights chalcone–pyrazole hybrids as promising therapeutic scaffolds. In particular, compound 3c emerges as a compelling lead candidate for further optimization and preclinical investigation as a dual‐action agent against malaria and inflammation.

This study reports an efficient synthesis of 6-(4-methoxyphenyl)-3-aryl-[1,2,4]triazolo[4,3-b]pyridazine derivatives via oxidative cyclization of the corresponding hydrazones using iodobenzene diacetate as a mild and metal-free oxidizing agent. The structures of the synthesized compounds were confirmed by 1H NMR, 13C NMR, FTIR, and mass spectrometry. Their in vitro anticancer activity was evaluated against the MCF-7 breast cancer cell line, where four compounds (7a, 7c, 7d, and 7f) exhibited notable cytotoxic effects. Molecular docking studies suggested favorable binding interactions of these compounds with several cancer-related targets, including human 17β-hydroxysteroid dehydrogenase, topoisomerase IIα, p73 tetramerization domain, Bcl2-xL, EGFR tyrosine kinase, and survivin. Docking of the complete compound series (7a-7j) further supported the observed activity trends. These findings indicate that triazolopyridazine derivatives represent promising scaffolds for further investigation as anticancer agents. IBD was used as an environment friendly reagent for the synthesis of 1,2,4-triazolo[4,3-b]pyridazines by oxidative cyclization of hydrazone derivatives. 1,2,4-Triazoles showed excellent anticancer activity against breast cancer Michigan Cancer Foundation-7 (MCF-7) cells. The molecular docking studies were carried out with several enzymes associated with breast cancer to find the effective binding of the synthesized compounds.

The present paper describes a comparative study of nitration of 2-arylimidazo[1,2-a]pyridines using synergistic approach of iodobenzene diacetate and copper nitrate trihydrate as a nitrating medium and a conventional mixed acid system (concentrated nitric acid/sulphuric acid). The devised methodologies afforded ortho-nitro products and C-3 nitrated products respectively. While a single example related to latter protocol has been previously reported, the present study expands it to a series of 3-nitro-2-arylimidazo[1,2-a]pyridines. A plausible mechanism involving electrophilic substitution via in situ generated nitronium ion is proposed for C-3 nitration and clear comparison with the synthesis of ortho-nitro products in synergetic approach is presented. The structures and regioselectivity of the products were confirmed by spectroscopic techniques, including 1H-NMR, 13C-NMR, mass spectrometry and FT-IR analysis. The protocol offers several advantages, such as moderate to higher yields (68–96

Chalcones are versatile scaffolds with broad pharmacological relevance, particularly as anti-inflammatory and anti-malarial agents. In the current investigation, a series of (3-arylediene-1-phenyl-1H-pyrazol-4-yl)acryloyl-4-hydroxy-6-methyl-2H-pyran-2-one analogs/1,3-diarylprop-2-en-1-ones were successfully synthesized, leveraging dehydroacetic acid (DHA) as the precursor molecule. The choice of DHA is strategic as it is a bioactive and highly versatile scaffold bearing a 4-hydroxy-6-methyl-2H-pyran-2-one moiety, which enhances structural diversity and provides multiple reactive sites for functionalization. Its inherent anti-microbial, anti-inflammatory, and anti-malarial potential offers an added advantage over conventional precursors, thereby increasing the likelihood of generating pharmacologically active chalcone hybrids. The synthetic protocol employed in this study involved the implementation of a Claisen condensation reaction, wherein DHA was reacted with formyl pyrazole to afford the corresponding chalcones, with yields ranging from moderate to good. The synthesized compounds were subjected to a rigorous characterization protocol, involving a battery of analytical techniques, including 1H-NMR, 13C-NMR, FT-IR, and HRMS analyses. Biological evaluation focused on anti-malarial and anti-inflammatory activities, while molecular docking (PyRx 0.8) was performed to explore binding interactions with cyclooxygenase-2 (COX-2; PDB ID: 3LN1) and enoyl-acyl-carrier-protein reductase (EACPR; PDB ID: 1NHG). Notably, compound 3c emerged as the most potent one within the synthesized series, exhibiting remarkable anti-inflammatory and anti-malarial potency, as evidenced by its IC50 values of 7.05 ± 0.17 µM and 0.95 ± 0.06 µM, respectively. Docking studies revealed strong binding affinities and favorable molecular interactions, supporting the observed bioactivities. This study highlights chalcone-pyrazole hybrids as promising therapeutic scaffolds. In particular, compound 3c emerges as a compelling lead candidate for further optimization and preclinical investigation as a dual-action agent against malaria and inflammation.

Breast cancer remains a leading cause of cancer mortality, demanding new chemotherapeutic options. A novel series of triazolopyridazine-pyrazole derivatives (11a-h) was synthesized and evaluated for cytotoxicity against MCF-7 breast cancer cells. Sulforhodamine B assay results identified compound 11e as the only active derivative, exhibiting moderate inhibition with a GI50 of 52 µg/mL, while all others were inactive (GI50 > 80 µg/mL). Molecular docking provided mechanistic support, revealing that 11e had the highest affinity for EGFR (PDB ID: 1M17; ˗10.1 kcal/mol, H-bond with MET769), along with strong interactions with Bcl-2 (2W3L; ˗9.9 kcal/mol) and p73 (2WTT; ˗9.5 kcal/mol). These findings suggest that 11e may exert anticancer effects via multi-target modulation, positioning it as a promising scaffold for further optimization.

Nitration of 2-arylimidazo[1,2-a]pyridines has been successfully carried out using a fast, straightforward, and one-step method. This innovative strategy was rigorously examined, focusing on the exclusive use of hypervalent iodine reagents or metallic salts under aqueous, non-aqueous conditions and grinding methods; ultimately leading to the desired outcomes through the combined use of widely used hypervalent iodine reagent iodobenzene diacetate and inexpensive copper nitrate trihydrate using organic solvent dichloromethane at room temperature. Herein, the iodobenzene diacetate reagent act as oxidant and copper nitrate as catalyst as well as the nitro group source. The model reaction method was expanded to a variety of substrates with different electron withdrawing and electron donating groups providing regioselective ortho-nitrated 2-arylimidazo[1,2-a]pyridines in significant yields. Further, the elucidation of the novel nitrated products was meticulously validated using a comprehensive array of analytical tools,1H-NMR, 13C-NMR, FT-IR, and mass spectral analysis. We conducted controlled experiments by blocking one of the possible attacking C-3 site to determine the specific product formed. The introduction of nitro functional group was facilitated through ortho C(sp2)-H activation strategy and the plausible mechanism for the nitration process has been proposed. Overall, the successful implementation of this methodology underscores its potential significance in advancing the synthesis of functionalized heterocycles.

ABSTRACT A series of fused [1,2,4]triazolo[4,3‐b]pyridazine derivatives was synthesized via hypervalent iodine‐mediated oxidative cyclization of hydrazone intermediates using iodobenzene diacetate under mild, metal‐free conditions. This method was applied to diverse 6‐(4‐nitrophenyl)‐substituted triazolopyridazines with various aryl and heteroaryl groups, producing the target compounds in good to excellent yields with broad substrate tolerance. All compounds were characterized by FT‐IR, 1 H NMR, 13 C NMR, and HRMS. Their antiproliferative activity was tested against the human triple‐negative breast cancer cell line MDA‐MB‐231 using the sulforhodamine B (SRB) assay. Compound 3c, containing a 3,4‐dimethoxyphenyl substituent, showed the highest activity, suggesting a beneficial effect of electron‐donating groups. Molecular docking against cancer‐related proteins showed favorable binding, especially with Topoisomerase IIα, though these computational results are preliminary and don't confirm the exact molecular target. This study presents an efficient synthesis strategy and identifies compound 3c as a promising lead for further biological and medicinal chemistry research.

Novel imidazo[2,1-b] thiazole-conjugated trans-2,3-dihydrofuran analogues were successfully synthesized through an efficient one-pot multicomponent cyclization strategy involving imidazo[2,1-b] thiazole-5carbaldehyde, dimedone, and phenacyl bromide. The reaction was carried out in acetonitrile using pyridine as the catalyst and triethylamine as the base, affording the desired hybrid derivatives in good to excellent yields under mild reaction conditions. The structures of the synthesized compounds were comprehensively characterized by 1H and 13C NMR nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), and infrared (IR) spectroscopy. The synthesized derivatives (4a-4i) were subsequently screened for their anti-oxidant and anti-inflammatory activities. All compounds demonstrated appreciable DPPH radical-scavenging activity, exhibiting percentage inhibition values in the range of 43.5-53.6% at the highest tested concentration (200 mu g/ mL). Among the evaluated compounds, derivative 4a, bearing dichloro substituents on the aromatic rings, exhibited remarkable anti-inflammatory potential with 95.05% inhibition, surpassing the activity of the reference drug celecoxib (81.66%). Furthermore, molecular docking investigations were performed to explore the binding interactions of the synthesized compounds with the target proteins, namely PDB ID: 1N3U and cyclooxygenase-2 (COX-2; PDB ID: 3LN1). The docking analyses revealed favorable binding affinities and significant molecular interactions within the active sites of the target proteins, providing valuable mechanistic insights into their biological activities. These findings offer a rational framework for the future design and optimization of imidazo[2,1-b] thiazole-based hybrids as promising therapeutic candidates.

AAnew series of pyridazinones (5a-5i) was synthesized and evaluated for antimicrobial activity through combined experimental and computational approaches. The target compounds were synthesized through nucleophilic substitution of pyridazinone intermediates with 2-chloroethanol. Antimicrobial screening against Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and fungi (Candida albicans and Aspergillus niger) revealed broad-spectrum efficacy. Some derivatives exhibited antifungal activity superior to fluconazole and demonstrated antibacterial potency comparable to ciprofloxacin. Structure-activity relationship analysis showed that halogenated derivatives (5d & 5f) enhanced Gram-negative and antifungal potency, the nitro group (5g) favored E. coli inhibition, whereas electron-donating substituents (5b, 5c & 5i) improved Gram-positive and antifungal activity. Molecular docking against C. albicans lanosterol 14-alpha-demethylase, CYP51 (protein data bank ID: 1KZN), demonstrated strong binding affinities (-8.3--9.3 kcal/mol), consistent with the experimental results. The most active derivatives formed key hydrogen bonds (ASP69, ASP352, and ARG442) and hydrophobic interactions (PHE303 and TYR72), validating the observed antimicrobial profiles.

A new series of Schiff base was synthesized via acid-catalyzed condensation of 1,3-diphenyl-1H-pyrazole-4-carbaldehydes with 4H-1,2,4-triazol-4-amine. The structures of the compounds were confirmed by 1H and 13C NMR spectroscopy. Antimicrobial screening revealed that nitro and bromo substituted derivatives exhibited the most potent antibacterial and antifungal activities, with minimum inhibitory concentrations comparable to ciprofloxacin and fluconazole. Structure-activity relationship (SAR) analysis indicated that electron-withdrawing substituents significantly enhanced biological activity, while methoxy-substituted analogues displayed moderate efficacy. Molecular docking studies against bacterial DNA gyrase (PDB ID: 1KZN) demonstrated strong binding affinities (from –8.8 to –9.4 kcal/mol) and stable interactions with active-site residues, corroborating the experimental findings. Collectively, these results establish pyrazole–triazole Schiff bases as promising antimicrobial scaffolds, providing a rational basis for future pharmacological development and structural optimization.

An efficient alternative methodology for the selective functionalization of anilides has been developed through the synergistic combination of PIDA and copper(II) acetate monohydrate in acetic acid. A comparative analysis with previously reported methodologies has been carried out. The developed protocol offer a practical and effective alternative to conventional methods employing expensive or toxic heavy-metal catalysts, highlighting the versatility and cost-effectiveness of copper salts in C-H functionalization reactions. The methodology was operationally simple and proceeds under mild reaction conditions, affording ortho-functionalized products in good to excellent yields. The obtained results were found to be consistent with reported palladium and cobalt-mediated protocols, while differ from Lewis acid promoted methodologies. Additional advantages of this approach include shorter reaction times, high reaction efficiency, and a simplified work-up procedure that avoids chromatographic purification. A plausible reaction mechanism involving ortho-assisted metal chelation has also been proposed.

The primary objective of this review is to outline the synthesis of pyrazolines and pyrazoles derived from 1,3‐diaryl Prop‐2‐en‐1‐ones as crucial precursors and to elucidate their potential biological activities. The diverse synthetic methodologies, including 1,3‐dielectrophile cyclization, 1,3‐dipolar cycloaddition/1,3‐H shift, Michael Addition reactions, [3+2] annulations, intramolecular condensation reactions, Atwal Reactions, and others, have been deliberated upon. Chalcones are considered important compounds because of their ketoethylenic group, and they include a wide array of compounds with various applications. The investigation of the biological evaluation of pyrazoline and pyrazole derivatives has emerged as a convincing area of research within pharmaceutical chemistry. This review may serve as a valuable resource for the development and design of novel, potent therapeutic agents, leveraging previously established strategies.

AIM:The aim of this study was to synthesize novel pyridine conjugates incorporating dehydroacetic acid via the Krohnke reaction and to evaluate their potential as anti-cancer agents. Materials & methods: The Krohnke reaction has previously been reported using acetic acid as the solvent, here we employed ethanol as the reaction medium. The trisubstituted pyridine derivatives were synthesized via a multistep procedure that involved the reaction of pyridinium bromide salts with chalcone derivatives of dehydroacetic acid. The synthesized hybrids were comprehensively characterized using a range of analytical techniques, including Nuclear Magnetic Resonance (NMR) spectroscopy, Fourier Transform Infrared (FT-IR) spectroscopy, and Mass Spectrometry (MS). RESULTS:These compounds were subjected to in vitro evaluation of their anti-cancer potential against MCF-7 (human breast cancer) and A-549 (human lung cancer) cell lines. The anti-cancer screening results indicate that the synthesized conjugates exhibit potent activity against MCF-7 cells and demonstrate moderate activity against A-549 cell lines. CONCLUSION:The analysis indicates a binding energy of -9.3 kcal/mol for the 7a derivative, which is closely comparable to that of the standard drug, which exhibits a binding energy of -9.9 kcal/mol.

A series of some new trans 2,3-dihydrofuran-linked pyrazole hybrids were synthesized from a convenient one-pot methodology. This procedure employs a sequential one-pot, two-step tandem reaction starting from pyridine, formylpyrazole, dimedone, and phenacyl bromide, with triethylamine serving as the base and proceeds efficiently in acetonitrile. The recently synthesized compounds were characterized through 1H and 13C NMR, Mass and IR spectroscopy and evaluated for their anti-inflammatory and anti-malarial potentials. Among the evaluated compounds, the derivative 4l, featuring a bromo group on the acetylphenyl and a methoxy group on the formylpyrazole phenyl ring, demonstrated potent anti-inflammatory activity with an IC50 value of 7.12 ± 0.03 μM. This potency was comparable to that of the standard drug diclofenac sodium (IC50 = 6.44 ± 0.02 μM). Additionally, 4l exhibited moderate anti-malarial properties with an IC50 value of 1.66 ± 0.04 μM, with respect to the reference drug quinine (IC50 = 0.26 ± 0.03 μM). Molecular docking studies were also performed to observe molecular interaction between the synthesized molecules and Enoyl-acyl-carrier-protein reductase (PDB ID: 1NHG) and Cyclooxygenase-2 inhibitors (3LN1). These studies provided valuable insights into the binding modes and affinities of the synthesized compounds, which may inform the design of future therapeutic agents.

The objective of this study was to synthesize 2-arylidene-6-methyl-2H-furo[3,2-c]pyran-3,4-diones (Aurones) and evaluate their potential as promising bioactive compounds with a broad spectrum of activities, including anti-cancer, anti-inflammatory, and anti-malarial properties. The aurones were synthesized through the bromination of chalcone analogs derived from dehydroacetic acid (DHA) via a multi-step procedure. Additionally, the synthesized compounds underwent comprehensive characterization utilizing a variety of analytical methodologies including Nuclear Magnetic Resonance (NMR), Fourier Transform Infrared Spectroscopy (FT-IR) and Mass Spectrometry (MS). Following this, they were subjected to in vitro evaluation to determine their efficacy against breast cancer cell lines MCF-7 and MDA-MB-231, as well as their potential anti-inflammatory and anti-malarial activities. Within the series, compound 5e exhibits noteworthy anti-malarial activity with IC50 of 1.02 +/- 0.05 mu M, while compound 5f demonstrates exceptional anti-inflammatory efficacy having IC50 at 7.23 +/- 0.11 mu M. All compounds exhibit low cytotoxicity concerning their anti-cancer activity, with TGI and GI50 values surpassing 80. Molecular docking investigations were additionally conducted utilizing the PyRx 0.8 software tool to analyze the molecular interactions between the synthesized compounds and three enzymes: EGFR tyrosine kinase (PDB ID: 1M17), Enoyl-acyl-carrier-protein reductase (PDB ID: 1NHG), and Cyclooxygenase-2 inhibitors (3LN1).

AIMS:This study aimed to design and synthesize novel dehydroacetic acid (DHA) based pyrazole - pyridine conjugates and evaluate their potential efficacy in combating inflammation and malaria. MATERIALS AND METHODS:A molecular hybridization strategy was employed to integrate the pyridine nucleus with two biologically active scaffolds, DHA and pyrazole. The target compounds were synthesized through a multi-step route involving the condensation of DHA with formyl-substituted pyrazoles to yield chalcone intermediates, followed by cyclization with malononitrile and ammonium acetate. The synthesized compounds were analyzed using spectroscopic techniques and tested in vitro for their anti-malarial and anti-inflammatory effects. Molecular docking studies were performed using PyRx 0.8 to predict binding interactions with key target enzymes - Enoyl-acyl-carrier-protein reductase (PDBID: 1NHG) and Cyclooxygenase-2 (PDB ID: 3LN1). RESULTS:Among the synthesized series, compound 5c exhibited the most potent activities, with an IC₅₀ of 0.96 ± 0.09 µM against Plasmodium falciparum and IC₅₀ of 7.23 ± 0.14 µM for significant anti-inflammatory activity. Docking results supported strong affinity toward both target enzymes. CONCLUSIONS:The findings demonstrate that DHA based pyrazole - pyridine hybrids are promising dual-action scaffolds with significant anti-malarial and anti-inflammatory potential.

A series of 1,2,4-triazolo[4,3-b]pyridazine derivatives has been synthesized via oxidative cyclization of pyridazinyl hydrazones in aqueous medium at room temperature. The use of hypervalent iodine (III) reagent as sole oxidant and water as solvent makes the synthetic procedure green. The structure of synthesized compounds was assigned using NMR, FTIR and Mass spectrometry. The in vitro cytotoxicity against the VERO cell line and anticancer activity against the MCF-7 breast carcinoma cell line was investigated. Among all the 1,2,4-triazolo[4,3-b]pyridazines, compounds bearing 2,5-dimethoxyphenyl, 2-furyl, 2-pyridyl and 3,4,5-trimethoxyphenyl at 3-position of triazole were found to be most potent against MCF-7 cell line. The active compounds were subjected to molecular docking at the active site of the NQO2 enzyme (PDB ID: 4ZVM). The docking scores ranging from − 6.69 to − 8.00 kcal/mol, along with key interactions such as hydrogen bonding, suggest a favorable fit of the potent compounds within the active site of the NQO2 enzyme.

Heterocyclic hybrid frameworks represent a burgeoning domain within the realms of drug discovery and medicinal chemistry, attracting considerable attention in recent years. Thiazole pharmacophore fragments, inherent in natural products such as peptide alkaloids, metabolites, and cyclopeptides, have demonstrated a broad spectrum of pharmacological potentials. Given their profound biological significance, a plethora of thiazole-based hybrids have been synthesized through the conjugation of thiazole moieties with bioactive pyrazole and pyrazoline fragments. This review systematically presents a compendium of robust methodologies for the synthesis of thiazole-linked hybrids, employing the (3 + 2) heterocyclization reaction, specifically the Hantzsch-thiazole synthesis, utilizing phenacyl bromide as the substrate. The strategic approach of molecular hybridization has markedly enhanced drug efficacy, mitigated resistance to multiple drugs, and minimized toxicity concerns. The resultant thiazole-linked hybrids exhibit a myriad of medicinal properties viz. anticancer, antibacterial, anticonvulsant, antifungal, antiviral, and antioxidant activities. This compilation of methodologies and insights serves as a valuable resource for medicinal chemists and researchers engaged in the design of novel thiazole-linked hybrids endowed with therapeutic attribute.

AbstractHydrazones are described as synthetic equivalents to the carbonyl group and possess high synthon value. Herein, we compile the oxidative transformation of hydrazones using ecologically and economically benign hypervalent iodine reagents of the last decade. In this field, the development of C─H functionalization reactions leading to the formation of heterocycles or functionalized hydrazones is a major advancement in recent years. The oxidative properties of hypervalent iodine reagents are exploited to form many bioactive heterocycles (pyrazole, pyrazoline, pyridazine, 1,2,4‐triazole, 1,2,3‐tiazole, 1,3,4‐oxadiazole, tetrazine, tetrazole, pyrrole) through intramolecular or intermolecular C─N, C─O, or N─N coupling. Functionalized heterocycles are also afforded via tandem cascade group transfer/cyclization reactions. The transfer of perfluoroalkyl, sulfoximidoyl, aryl, and halogen groups is achieved using hypervalent iodine reagents as group donors or oxidants in combination with other group‐donating agents. The Togni reagent is the preferred choice for trifluoromethyl group donation, with or without a metal catalyst. Moreover, rearrangement reactions such as acyl migration and the diazotization of hydrazones are also achieved.