Current Medicinal Chemistry - Volume 33, Issue 5, 2026

More robust 4-substituted 7-chloroquinolines have been investigated for their diverse properties. However, there is still no systematic study that correlates the effects of the side chain at the 4-position of chloroquine and hydroxychloroquine derivatives with their lipophilicity, antimicrobial and toxicity properties.

To this end, a cleaner and facile approach was planned to obtain nineteen 4- substituted 7-chloroquinolines, whose influence of the substituent group and side chain extension at the 4-position on their properties was studied.

4-Alkoxy/amino-7-chloroquinolines were prepared by a nucleophilic aromatic substitution (SNAr) reaction between 4,7-dichloroquinoline and alcohols/amines, evaluated for their in silico ADMET test, in vitro antimicrobial activity against Gram-(+) and Gram-(−) bacteria, and Candida albicans fungus, and in vitro toxicity on Artemia salina larvae.

4-Alkoxy/amino-7-chloroquinolines were obtained in yields ranging from 81 to 100%. The best results showed antimicrobial activity against Pseudomonas aeruginosa for 4-amino-7-chloroquinolines 6-8, with halos greater than 20 mm, and against C. albicans for 4-amino-7-chloroquinolines 1-3, with halos close to 30 mm. A correspondence between Minnow toxicity prediction and in vitro toxicity on A. salina larvae was observed, where compounds 3 and 14, with R = Pent, were both predicted to have high acute toxicity (log LC50 < -0.3) and classified as highly toxic (LC50 < 100 µg mL^-1). It seems that increased lipophilicity in the side chain is harmful to A. salina larvae.

Considering the results for compounds 1-3 and 6-8 with greater activity against C. albicans and P. aeruginosa, respectively, especially for 4-amino-7-chloroquinolines 6 and 7, which are slightly toxic on A. salina larvae (LC50 500-1000 µg mL^-1), their antimicrobial studies deserve to be continued by the determination of Minimum Inhibitory Concentration (MIC) values.

Several pathological conditions, including glaucoma, malignant brain tumors, and renal, gastric, and pancreatic carcinomas, are commonly associated with carbonic anhydrase type II (CA-II). Additionally, CA-II plays a critical role in regulating bicarbonate concentration in the eyes. The inhibition of CA-II reduces aqueous humor production and thus lowers intraocular pressure associated with glaucoma.

This study aimed to synthesize potent CA-II inhibitors, 5-nitro-1H-benzo[d]imidazole-2(3H)-thione (5NBIT) and acylhydrazone derivatives (1-13).

In this study, a new series of potent CA-II inhibitors, 5-nitro-1H-benzo[d]imidazole-2(3H)-thione (5NBIT) and acylhydrazone derivatives (1-13), were synthesized and characterized by IR, NMR, UV and mass spectroscopy and evaluated against bovine carbonic anhydrase-II (bCA-II).

Interestingly, most of the compounds showed better inhibition than the standard drug, acetazolamide (IC50: 18.2±0.51 µM), such as compounds 1 (IC50: 10.5±0.81 µM), 2 (IC50: 11.3±0.36 µM), 3 (IC50: 16.5±0.53 µM), 4 (IC50: 15.8±1.02 µM), 5 (IC50: 13.7±1.03 µM), and 9 (IC50: 12.2±1.03 µM). Among the synthesized compounds, compound 7 (IC50: 8.2±0.32 µM) exhibited the highest and compound 6 (IC50: 27.6±0.39 µM) showed the lowest inhibition. Structure-activity relationships suggest that the presence of nitro group on the phenyl ring contributed significantly to the overall inhibitory activity. Molecular docking of all the active compounds was performed to predict their binding behavior, which indicated good agreement between docking and experimental findings. Moreover, the MD simulation of compound 7 also showed excellent binding behavior and binding energy within the binding cavity of bCA-II.

These findings suggest that the synthesized 5NBIT and acylhydrazone derivatives exhibited potent CA-II inhibition, with several compounds outperforming the standard drug acetazolamide. These results provide valuable insights for the development of novel CA-II inhibitors with potential therapeutic applications in glaucoma and other related conditions.

Staphylococcus aureus infections have become a significant public health issue due to increasing the resistance against known antibiotics, especially by Methicillin-Resistant Staphylococcus aureus (MRSA). Fluoroquinolones are broad-spectrum class of antibiotics mostly utilized in treating various bacterial infections and those caused by S. aureus. Reported data indicated that mutations of Ser84 to Leu, Ser85 to Pro and Glu88 to Lys in DNA gyrase A enzyme are the major cause of fluoroquinolone resistance against S. aureus. Therefore, the development of a novel targeted molecule with potential activity against mutant S. aureus is essential. The antibacterial activity of quinoline-clubbed hydrazone derivatives against S. aureus is noteworthy. However, the mechanism of action of quinoline hydrazone derivatives has not been reported by inhibiting these common mutations of DNA gyrase A.

In this concern, some quinoline hydrazone derivatives as antibacterial agents reported by several research groups have been further studied as mutated S. aureus DNA gyrase A (Pdb id: 8bp2) inhibitors using in silico techniques viz., molecular docking, MD simulation, DFT analysis, and ADMET predictions.

Among the studied compounds, 42, 43, 48 and 49 were found to be the most active and showed the highest docking score (-7.71 to -9.29 kcalmol^-1) by interaction with mutant (Leu84 and Pro85) S. aureus DNA gyrase A. Further, MD simulation results indicated that these compounds exhibited good stability with the targeted macromolecule under dynamic conditions. The most active compound 49 (ʌE = 0.159 eV) attributed to its lower HOMO-LUMO gap, which was an indicator of a potential inhibitor of fluoroquinolone- resistant S. aureus DNA gyrase A enzyme. ADMET prediction study emphasized that both compounds showed a significant safety profile.

The future perspective emphasized that compounds 42, 43, 48 and 49 could be developed as novel inhibitors against fluoroquinolone-resistant DNA gyrase A enzyme on the completion of drug discovery approaches.

Over 85% of biologically active compounds are heterocycles or contain heterocyclic groups, underscoring their vital importance in contemporary drug development. Among them, nitrogen-containing derivatives, such as pyridines and pyrimidines, are considered privileged structures in approved drugs or are extensively studied due to their promising therapeutic effects.

In the current work, we would like to verify the hypothesis that incorporating heterocyclic pharmacophores into derivatives of pyrimidine-2(1H)-thione (PMT), 2-pyridone (P), pyridine-2(1H)-thione (PT), dihydropyrimidine-2(1H)-thione (DHPMT), dihydropyridin-2(1H)-one (DHP), and dihydropyridine-2(1H)-thione (DHPT) rings enhances antitumor activity.

A range of novel pyridine- and pyrimidine-based compounds were synthesized and assessed for their anticancer properties against the melanoma A375 cell line. The two most potent compounds (16b and 29) were then chosen for further evaluation of their effects on non-cancerous human dermal fibroblasts, cancer cell apoptosis, cell cycle phase distribution, and tubulin polymerization. Furthermore, in silico analyses were performed to assess the pharmacokinetics, toxicity, drug-likeness, and molecular target of the selected compounds.

Among the 33 compounds tested, pyridine analogs 16b and 29 demonstrated the strongest antiproliferative activity (with IC50 values of 1.85 ± 0.44 µM and 4.85 ± 1.67 µM, respectively) and selectivity (SI=65.08 and SI> 100, respectively) against cancer cells. Additional studies revealed that compound 16b, which features a thiophene ring at the C-5 position and a 3,4,5-trimethoxyphenyl (TMP) group, showed the most promising cell cycle arrest and tubulin polymerization inhibition (IC50=37.26 ± 10.86 µM), resulting in cancer cell apoptosis. In silico ADMET analysis confirmed the drug- likeness of the synthesized compounds.

This research reinforced the significance of heterocyclic rings as valuable pharmacophores. Additionally, it highlighted the antiproliferative and antimitotic potential of modified pyridine derivatives.

Dyshomeostasis of Cu²⁺ and abnormal interactions between Cu²⁺ and β Amyloid peptide (Aβ) can promote Aβ aggregation and oxidative stress, which are considered to trigger Alzheimer’s Disease (AD). Metal chelating therapy is a promising approach for the treatment of AD.

In this study, 2-(2-hydroxyphenyl)benzazoles were synthesized via microwave irradiation promotion. Chelators inhibiting Cu²⁺-induced Aβ aggregation were determined through turbidity assay and BCA protein assay, while anti-oxidants were detected via HRP/Amplex red assay and fluorescent probe of DCFH-DA. Cell viability was measured by MTT assay.

The bio-activity for inhibiting Cu²⁺ induced-Aβ aggregation of chelators S-1, S-3, S-4, S-5, S-7, S-10, N-5, N-9, N-10 O-2, O-4, X-N-2 was better than that of CQ. The ability of the chelators (S-1, S-10, O-2, O-5, N-9, and X-N-2) to decrease the level of ROS in Aβ+Cu²⁺ treated SH-SY5Y cells was better than that of CQ. The ability to attenuate Aβ-mediated cytotoxicity in SH-SY5Y cells of S-10 (O-2, O-5, and N-9) was better than that of CQ.

After the evolution of the bio-activities for the treatment of AD in vitro, it was found that 4 chelators (S-10, O-2, O-5, and N-9) exhibited better bio-activities than CQ in all aspects.

Chemotherapy remains essential despite advances in immunotherapy, radiotherapy, and biological therapy. However, the wide range of chemical drugs is limited by a narrow therapeutic index, low selectivity, and the development of resistance. In this regard, new high-efficiency drugs are in extremely high demand. The indazole moiety, a scaffold found in many biologically active compounds, was selected for use in new drug design.

Six new indazole derivatives were synthesized via Suzuki-Miyaura coupling starting from bromoindazole. Their antiviral (against influenza A and SARS-CoV-2), antibacterial (against M. tuberculosis), and antiproliferative activities (against neuroblastoma, glioma, leukemia cell lines) were evaluated in vitro. Acute toxicity was assessed in mice of both sexes via single intragastric administration, with toxicometric parameters and pathomorphological changes studied.

6-(1H-pyrazol-4-yl)-1H-indazole (8) suppressed the reproduction of the influenza virus at non-toxic doses to the MDCK cells and showed cytotoxicity against cancer cell lines, with an IC50 between 4 and 14 µM. However, it exhibited significant acute toxicity in mice (LD50 40 mg/kg), causing systemic organ damage.

Derivative 8 demonstrated promising antiviral and antiproliferative activities but exhibited considerable acute toxicity in vivo. The antiviral efficacy, although lower than oseltamivir, is meaningful and justifies further optimization and investigation. Its antibacterial activity against M. tuberculosis adds to its potential as a multifunctional agent.

While derivative 8 has shown potential as an antiviral and anticancer agent, its high toxicity highlights the need for further studies to define a safe and effective therapeutic window. Overall, the indazole scaffold remains a valuable platform for the development of new therapeutic compounds.

Tyrosinase, a copper-containing enzyme, is responsible for melanin production, and its overactivity can lead to hyperpigmentation.

This study aimed to evaluate triazolothiadiazoles (3a-h, 4a-f) and triazolothiadiazines (5a-h) against human and mushroom tyrosinase isozymes.

Several derivatives, such as 3a-3b, 3d, 4c-4f, 5d, and 5e, were identified as potent and selective inhibitors of mushroom tyrosinase, with IC50 values ranging from 1.9 to 15.2 µM. Similarly, compounds 3f, 4b, 5a, and 5b effectively inhibited human tyrosinase, with IC50 values between 12.6 and 18.5 µM. Mechanism-based studies revealed that these active compounds exhibited competitive inhibition against both isozymes without any cytotoxic effects. In silico analysis further demonstrated that these compounds fit well into the active site of both tyrosinase isozymes.

Additionally, the pharmacokinetic profile of these compounds highlighted promising drug-like properties, making them potential candidates for the development of effective therapeutics for skin disorders.

A series of benzylidene derivatives of fenobam and its thio analogues (1-22) have been evaluated for their cytotoxicity against breast cancer (MCF-7, MDA-MB-231), ovarian cancer (A2780, SKOV-3) and cervical cancer (HELA) cell lines.

These compounds (1-22) exhibited 72-83% inhibition of Erk activity against the ovarian cancer cell line (A2780). Compounds 3 and 20 showed the highest DNA damage effect in comet assay against the A2780 cancer cell line as compared to the other tested analogues (4, 8, 11, 12, and 13) by using % Tail DNA and OTM. Compounds 3, 4, and 11 showed significant activities and selectivity towards COX-2 with 78%, 97%, and 89% inhibition, as compared to 17%, 57%, and 26% inhibition against COX-1 isoenzyme, respectively.

Interestingly, molecular docking scores were also in very good agreement with the experimental results regarding discriminating the selectivity index of the tested compounds against COX-1 & COX-2 enzymes. Further molecular dynamics (MD) simulation study revealed that the most selective compound, 13, binds with the COX-2 enzyme in a similar fashion to that of Rofecoxib, which was further supported by their MD-based free binding energies (MM-GBSA) of -49.76 ± 4.27 kcal/mol, and -44.84 ±3.78 kcal/mol, respectively.

Moreover, in silico ADMET predictions showed adequate properties for these compounds, making them promising leads worthy of further optimization.

Diabetes mellitus (DM) is a chronic metabolic disorder that seeks treatment instead of available mitigative therapy.

Six (E)-3-(aryl)-1-phenylprop-2-en-1-one chalcones were synthesized and characterized through various spectroscopic techniques. Their anti-diabetic potential was examined through in vitro (α-glucosidase and α-amylase inhibition assays), in vivo (alloxan-induced hyperglycemia), and in silico studies.

All the chalcones derivatives significantly inhibited α-glucosidase and α-amylase. Compounds 11 (IC50 = 1.10 ± 0.02) and 13 (IC50 = 3.25 ± 0.10 µM) exhibited the most potent activity against α-glucosidase. The effect of compounds 11 and 13 was also significant against α-amylase with IC50 of 13.2 ± 0.50 and 10.2 ± 0.4 µM, respectively. In alloxan-induced hyperglycemic model, a significant (p<0.001) reduction in blood glucose level (BGL) was observed by compounds 10, 11 and 14 with maximum percent inhibition of 47.48, 47.22 and 47.55, respectively. In the oral glucose tolerance test, a continuous reduction in BGL was noted at 60 minutes. No negative effect was seen on lipid profile, and in liver and renal function tests. However, a slight gain in body weight was noted. Moreover, docking result indicates good interaction of these molecules with the target enzymes, α-glucosidase and α-amylase.

These results demonstrate that all these molecules have significant anti-diabetic potential.

The disability and mortality related to Parkinson's disease (PD), a neurodegenerative disease, are increasing globally at a faster rate than other neurological disorders. With no permanent cure for PD, there is an urgent need to develop novel and effective anti-PD drugs.

Targeting monoamine oxidases (MAO), which catalyze the breakdown of neurotransmitters, is one way to treat neurodegenerative diseases. In this context, an initial molecular docking of twenty designed sulfonyl derivatives of benzimidazole against monoamine oxidase B (MAO-B) associated with PD was conducted using AutoDock Vina.

The results were compared with those of the conventional inhibitors, selegiline and rasagiline. Based on the docking score, the in silico pharmacokinetic properties (ADME), drug-likeness, and toxicity profiles of the newly synthesized molecules were examined using SwissADME, PreADMET, ProTox-3.0, vNN, and ADMETlab web tools. Then, twelve potential derivatives were synthesized and characterized by IR, ¹H-NMR, ¹³C-NMR, ¹⁹F-NMR (for some compounds), and mass spectrometry. Derivatives 2cj and 1bj were the two molecules having the best binding affinity of -11.9 and -11.8 kcal/mol, respectively, against MAO-B, exhibiting a higher binding affinity compared to that of some commercially available drugs. A 50 ns MD simulation run was performed to observe the stability of the top two docked complexes, MAO-B-2cj and MAO-B-1bj, in order to further validate the efficacy of those two substances. Moreover, the MM-PBSA method was used to calculate the final, binding free energy of the simulated (MAO-B-2cj) complex.

This study indicates that the binding affinity of most of the hits was superior to that of known MAO inhibitors; therefore, these newly synthesized benzimidazole derivatives may be developed into essential drug candidates for the treatment of PD.