Antimicrobial resistance has become a significant threat to global public health, thus precipitating an exigent need for new drugs with improved therapeutic efficacy. In this regard, molecular ...hybridization is deemed as a viable strategy to afford multi-target-based drug candidates. Herein, we report a library of quinoline—1
H
-1,2,3-triazole molecular hybrids synthesized via copper(I)-catalyzed azide-alkyne 3 + 2 dipolar cycloaddition reaction (CuAAC). Antimicrobial evaluation identified compound
16
as the most active hybrid in the library with a broad-spectrum antibacterial activity at an MIC
80
value of 75.39 μM against methicillin-resistant
S. aureus
,
E. coli
,
A. baumannii,
and multidrug-resistant
K. pneumoniae
. The compound also showed interesting antifungal profile against
C. albicans
and
C. neoformans
at an MIC
80
value of 37.69 and 2.36 μM, respectively, superior to fluconazole. In vitro toxicity profiling revealed non-hemolytic activity against human red blood cells (hRBC) but partial cytotoxicity to human embryonic kidney cells (HEK293). Additionally, in silico studies predicted excellent drug-like properties and the importance of triazole ring in stabilizing the complexation with target proteins. Overall, these results present compound
16
as a promising scaffold on which other molecules can be modeled to deliver new antimicrobial agents with improved potency.
Graphic abstract
The widely held belief in the potential superiority of agents capable of modulating multiple biological targets has led to the adoption of molecular hybridization as an effective technique in the ...realm of drug discovery and development ...
A library of pyrazole–thiazolidinone conjugates was synthesized using a molecular hybridization approach through a Vilsmeier–Haack reaction. The compounds were tested for anti-microbial activity ...against two Gram-positive bacteria (
Staphylococcus aureus
and methicillin-resistant
Staphylococcus aureus
) and four Gram-negative bacteria (
Escherichia coli
,
Salmonella typhimurium
,
Klebsiella pneumonia
and
Pseudomonas aeruginosa
). Among the compounds tested
, 3
-
((2,4
-
dichlorophenyl)
-
1
-
(2,4
-
dinitrophenyl)
-
1H
-
pyrazol-yl)methylene)hydrazinecarbothioamide
(
3a
) and
2
-
((3
-
(2
-
chlorophenyl)
-
1
-
(2,4 dinitrophenyl)
-
1H
-
pyrazol
-
4
-
yl)methyleneamino)thiazolidin
-
4
-
on
e (
4b
) emerged as the most potent anti-microbial compounds with minimum bactericidal concentrations of < 0.2 µM against MRSA and
S. aureus
. Structure–activity relationship analysis further revealed that the presence of 2,4-dichloro moiety surprisingly influenced the activity of the compounds. Molecular docking studies of the compounds into the crystal structure of topoisomerase II and topoisomerase IV suggest that compounds
3a
and
4b
preferably interact with the targets through hydrogen bonding.
The crystal and molecular structure of 5-(4-chlorophenyl)-2-amino-1,3,4-thiadiazole 3 was reported, which was characterized by various spectroscopic techniques (FT-IR, NMR and HRMS) and ...single-crystal X-ray diffraction. The crystal structure 3 (C
H
ClN
S) crystallized in the orthorhombic space group Pna2
and the unit cell consisted of 8 asymmetric molecules. The unit cell parameters were a = 11.2027(2) Å, b = 7.6705(2) Å, c = 21.2166(6) Å, α = β = γ = 90°, V = 1823.15(8) Å
, Z = 8. In addition, the structural geometry (bond lengths, bond angles, and torsion angles), the electronic properties of mono and dimeric forms of compound 3 were calculated by using the density functional theory (DFT) method at B3LYP level 6-31+ G(d,p), 6-31++ G(d,p) and 6-311+ G(d,p) basis sets in ground state. A good correlation was found (R
= 0.998) between the observed and theoretical vibrational frequencies. Frontier molecular orbitals (HOMO and LUMO) and Molecular Electrostatic Potential map of the compound was produced by using the optimized structures. The NBO analysis was suggested that the molecular system contains N-H…N hydrogen bonding, strong conjugative interactions and the molecule become more polarized owing to the movement of π-electron cloud from donor to acceptor. The calculated structural and geometrical results were in good rational agreement with the experimental X-ray crystal structure data of 1,3,4-thiadiazol-2-amine, 3. The compound 3 exhibited n→π* UV absorption peak of UV cutoff edge, and great magnitude of the first-order hyperpolarizability was observed. The obtained results suggest that compound 3 could have potential application as NLO material. Therefore, this study provides valuable insight experimentally and theoretically, for designing new chemical entities to meet the demands of specific applications.
Chalcones are an interesting class of compounds endowed with a plethora of biological activities beneficial to human health. These chemotypes have continued to attract increased research attention ...over the years; hence, numerous natural and synthetic chalcones have found with interesting anticancer activities through the inhibition of various molecular targets including ABCG2, BCRP, P-glycoprotein, 5α-reductase, Androgen Receptor (AR), Histone Deacetylases (HDAC), Sirtuin 1, proteasome, Vascular Endothelial Growth Factor (VEGF), Cathepsin-K, tubulin, CDC25B phosphatase, Topoisomerase, EBV, NF-κB, mTOR, BRAF, and Wnt/β-catenin. Moreover, the study of intrinsic mechanisms of action, particularly relating to specific cellular pathways and modes of engagement with molecular targets, may help medicinal chemists to develop more effective, selective, and cost-effective chalcone-based anticancer drugs. This review, therefore, sheds light on the effect of structural variations on the anticancer potency of chalcone hybrids reported in 2018-2019 alongside their mechanism of action, molecular targets, and potential impacts on effective cancer chemotherapy.
•StEP recombination is a successful tool for recombining beneficial traits into a single enzyme.•Arginine is a crucial amino acid for enhanced thermal stability but it contributes to diminished ...catalytic activity.•Molecular modelling showed that alpha-helical regions and interactions created by point mutations stabilise the protein.
Mutant xylanases, G41 and G53, were generated by random mutagenesis of Thermomyces lanuginosus xylanase DSM 5826 (xynA) in a previous study. Incubation at 90min showed that G41 had 75% activity at 80°C and G53 had 93% activity at pH 10. In order to create xylanase variants possessing both thermal and alkaline stability in a single enzyme, G41 and G53 served as templates for DNA shuffling using the StEP recombination method. One of the resulting StEP recombinants, S340, retained 54% stability at 80°C and 60% stability at pH 10 with three resulting amino acid mutations. Another StEP recombinant, S325, displayed 85% stability at 80°C and 60% stability at pH 10 and DNA sequencing showed that it inherited mutations from both parents. All thermostable variants displayed an increase in arginine content with poor enzyme activity. Thus, the StEP recombination method successfully recombined mutations into two xylanases that were more robust than their parent counterparts. Additionally, the 3D-models of the wild type T. lanuginosus xynA (xyl_ext) and its variants, G41 and S325, were predicted using I-TASSER and then subjected to molecular dynamics (MD) simulations at 300K for a deeper understanding of their structural features. The results from the predicted 3D models show clearly the presence of α-helical regions in the N-terminal residues of the xyl_ext, G41 and S325. Moreover, the MD analysis suggests that the presence of additional residues (1–31) and point mutation induces slight structural changes with the stability of the protein being evenly distributed over the whole structure.
In recent years, transamidation has been an essential topic in the formation of amide bonds over the conventional route due to chemoselectivity and greenside products. So many groups have disclosed ...new amide transformation techniques. Transamidation is typically classified into two categories based on amide activation: activated amide and unactivated amide. We conducted a review of the pertinent literature that discusses the cross amidation reactions of unactivated amides employing a variety of reagents, enabling contemporary research professionals to overcome synthetic barriers.
Graphical abstract
Diabetes mellitus (DM) is a multifaceted metabolic disorder that remains a major threat to global health security. Sadly, the clinical relevance of available drugs is burdened with an upsurge in ...adverse effects; hence, inhibiting the carbohydrate-hydrolyzing enzymes α-glucosidase and α-amylase while preventing oxidative stress is deemed a practicable strategy for regulating postprandial glucose levels in DM patients. We report herein the α-glucosidase and α-amylase inhibition and antioxidant profile of quinoline hybrids 4a–t and 12a–t bearing 1,3,4-oxadiazole and 1,2,3-triazole cores, respectively. Overall, compound 4i with a bromopentyl sidechain exhibited the strongest α-glucosidase inhibition (IC50 = 15.85 µM) relative to reference drug acarbose (IC50 = 17.85 µM) and the best antioxidant profile in FRAP, DPPH, and NO scavenging assays. Compounds 4a and 12g also emerged as the most potent NO scavengers (IC50 = 2.67 and 3.01 µM, respectively) compared to gallic acid (IC50 = 728.68 µM), while notable α-glucosidase inhibition was observed for p-fluorobenzyl compound 4k (IC50 = 23.69 µM) and phenyl-1,2,3-triazolyl compound 12k (IC50 = 22.47 µM). Moreover, kinetic studies established the mode of α-glucosidase inhibition as non-competitive, thus classifying the quinoline hybrids as allosteric inhibitors. Molecular docking and molecular dynamics simulations then provided insights into the protein–ligand interaction profile and the stable complexation of promising hybrids at the allosteric site of α-glucosidase. These results showcase these compounds as worthy scaffolds for developing more potent α-glucosidase inhibitors with antioxidant activity for effective DM management.
Cancer is considered one of the leading causes of death globally, especially patients with lung, pancreatic, or brain tumors are most likely to die of cancer, and patients with prostate and breast ...cancer are at a high risk of noncancer death. As a result, there is ongoing research regarding developing new, safe, and efficient anticancer agents. Coumarin-based naturally occurring compounds possess a broad spectrum of activity in medicinal chemistry, such as anticancer, anti-inflammatory, antimicrobial, antioxidant agents, etc. Many researchers have synthesized coumarinbased novel therapeutic agents via molecular hybridization technique, which offers an excellent opportunity to develop novel compounds with improved biological activities by incorporating two or more pharmacophores. This review aims to shed light on the recent developments of coumarin-based anticancer hybrid derivatives and their Structure-Activity Relationships (SAR). This review serves as a medium that medicinal chemists could utilize to design and synthesize coumarin derivatives with significant pharmacological value as future anticancer agents.
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