Malaria remains a significant global health concern causing numerous fatalities and the emergence of antimalarial drug resistance highlights the urgent need for novel therapeutic options with ...innovative mechanisms of action and targets. This study aimed to design potential inhibitors of
6-pyruvoyltetrahydropterin synthase (
PTPS), synthesize them, and experimentally validate their efficacy as antimalarial agents. A structure-based approach was employed to design a series of novel derivatives, including amidinyl, amidoximyl and hydroxamic acid analogs (
,
,
, and
), with a focus on their ability to bind to the Zn
present in the active site of
PTPS. The syntheses of these compounds were accomplished through various multi-step synthetic pathways and their structural identities were confirmed using
H and
C NMR spectra, mass spectra, and elemental analysis. The compounds were screened for their antiplasmodial activity against the NF54 strain of
and
cytotoxicity testing was performed using L-6 cells. The
acute toxicity of the compounds was evaluated in mice. Docking studies of the compounds with the 3D structure of
PTPS revealed their strong binding affinities, with compound
exhibiting notable metal-acceptor interaction with the Zn
in the protein binding pocket thereby positioning it as a lead compound for
PTPS inhibition. The
antiplasmodial studies revealed moderate efficacies against the
NF54 strain, particularly compounds
and
which displayed IC
< 0.2 μM. No significant cytotoxicity was noted on the L-6 rat cell line. Moreover,
studies suggested that compound
exhibited both safety and efficacy in treating rodent malaria. The identified lead compound in this study represents a possible candidate for antimalarial drug development and can be further explored in the search for alternative antifolate drugs to combat the malaria menace.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Benzimidazole derivatives are crucial structural scaffolds found in diverse libraries of biologically active compounds which are therapeutically useful agents in drug discovery and medicinal ...research. They are structural isosteres of naturally occurring nucleotides, which allows them to interact with the biopolymers of living systems. Hence, there is a need to couple the latest information with the earlier documentations to understand the current status of the benzimidazole nucleus in medicinal chemistry research. This present work unveils the benzimidazole core as a multifunctional nucleus that serves as a resourceful tool of information for synthetic modifications of old existing candidates in order to tackle drug resistance bottlenecks in therapeutic medicine. This manuscript deals with the recent advances in the synthesis of benzimidazole derivatives, the widespread biological activities as well as pharmacokinetic reports. These present them as a toolbox for fighting infectious diseases and also make them excellent candidates for future drug design.
Recent advances in the chemistry and pharmacological activities of benzimidazole scaffolds are reported, qualifying them as arsenals for combating infectious diseases and making them resourceful tools and a wheel of fortune in therapeutic medicine for drug design.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Quinazolin-4(3
)-one derivatives have attracted considerable attention in the pharmacological profiling of therapeutic drug targets. The present article reveals the development of arylidene-based ...quinazolin-4(3
)-one motifs as potential antimicrobial drug candidates.
The synthetic pathway was initiated through thermal cyclization of acetic anhydride on anthranilic acid to produce 2-methyl-4H-3,1-benzoxazan-4-one 1, which (upon condensation with hydrazine hydrate) gave 3-amino-2-methylquinazolin-4(3
)-one 2. The reaction of intermediate 2 at its amino side arm with various benzaldehyde derivatives furnished the final products, in the form of substituted benzylidene-based quinazolin-4(3
)-one motifs 3a-l, and with thiophene-2-carbaldehyde to afford 3 m. The purified targeted products 3a-m were effectively characterized for structural authentication using physicochemical parameters, microanalytical data, and spectroscopic methods, including IR, UV, and
H- and
C-NMR, as well as mass spectral data. The substituted arylidene-based quinazolin-4(3
)-one motifs 3a-m were screened for both
and
antimicrobial properties against selected bacteria and fungi. The in silico studies carried out consisted of predicted ADMET screening, molecular docking, and molecular dynamics (MD) simulation studies. Furthermore,
experimental validation was performed using the agar diffusion method, and the standard antibacterial and antifungal drugs used were gentamicin and ketoconazole, respectively.
Most of the compounds possessed good binding affinities according to the molecular docking studies, while MD simulation revealed their levels of structural stability in the protein-ligand complexes. 2-methyl-3-((thiophen-2-ylmethylene)amino) quinazolin-4(3
)-one 3 m emerged as both the most active antibacterial agent (with an minimum inhibitory concentration (MIC) value of 1.95 μg/mL) against Staphylococcus aureus and the most active antifungal agent (with an MIC value of 3.90 μg/mL) against
,
, and
.
Coumarin is an oxygen-containing heterocyclic compound of great medicinal important and high versatility in electronic and material science research. Incorporation of pyrimidine as a linker on ...coumarin is a way to provide improved application in solar cell research by extension of unsaturation for improved electronic transition. Convention synthesis approach is common in organic synthesis but have some disadvantages like affecting the eco-system due to discharge of toxic chemical during the process. On the other hand, microwave irradiation is eco-friendly and accelerates synthesis to afford great products following interesting reaction schemes and steps at reduced time. Hence, microwave assisted synthesis of novel coumarin-based 5,6-dihydropyrimidin-2(1H)-one derivatives was herein achieved via a three-step synthetic approach. The reaction was initiated with catalyst supported multicomponent reaction to produce 3-acetylcoumarin 7 which upon condensation with five aromatic aldehydes furnished chalcones 8a-e. Microwave assisted reaction of chalcones 8a-e with lone pair donor, urea led to the formation of the targeted coumarin-based 5,6-dihydropyrimidin-2(1H)-one 9a-e in good-to-excellent yields. The structures were established using spectroscopic data and notable physical properties and the results obtained were consistent with the expected structure of the products. The compounds will be good for further study to authenticate their applications in drug design and material science research.
Benzimidazole derivatives are known to represent a class of medicinally important compounds which are extensively used in drug design and catalysis. A series of 2-substituted benzimidazole ...derivatives 10a-i was herein synthesized from the reaction of o-phenylenediamine with some amino acids using ameliorable pathway. The chemical structures of the synthesized compounds were confirmed by IR, UV, 1H-NMR, 13C-NMR, Mass spectral and analytical data. The compounds were investigated for their antimicrobial activity alongside gentamicin clinical standard. The results showed that this skeletal framework exhibited marked potency as antimicrobial agents. The most active compound was 1H-benzodimidazol-2-yl)methanamine, 10a.
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The aim of this present study was to synthesize 2-substituted and 1,2-disubstituted benzimidazole derivatives to investigate their antibacterial diversity for possible future drug ...design. The structure-based design of precursors 2-(1H-benzimidazol-2-yl)aniline 1, 2-(3,5-dinitro phenyl)-1H-benzimidazole 3 and 2-benzyl-1H-benzimidazole 5 were achieved by the condensation reaction of o-phenylenediamine with anthranilic acid, 3,5-dinitrophenylbenzoic acid, and phenylacetic acid, respectively. The precursors 1, 3 and 5, upon reaction with six different electrophile-releasing agents, furnished the corresponding 2-substituted benzimidazole, 2a-f and 1,2-disubstituted benzimidazole derivatives 4a-f and 6a-f, respectively. The structural identity of the targeted compounds was authenticated by elemental analytical data and spectral information from FT-IR, UV, 1H, and 13C NMR. The outcome of the findings from the in vitro screening unveiled 2-benzyl-1-(phenylsulfonyl)-1H-benzimidazole 6b as the most active derivative with lowest MIC value of 15.63µg/mL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pyrimidine, an essential component of nucleic acid is currently reported for its potential application in Acquired Immune Deficiency Syndrome (AIDS) chemotherapy. Also, pyrazole nucleus, a versatile ...heterocyclic compound is gaining more attention in drug designs owing to its pharmacological therapeutic potentials. Hence, this present study deals with cost effective synthesis of 6-methyl-4-phenyl-5-(substituted-5-phenyl-4H-pyrazol-3-yl)-3,4-dihydropyrimidine-2(1H)-thione derivatives which are concisely known as pyrazole-based pyrimidine scaffolds. The multicomponent reaction of benzaldehyde, acetyl acetone and thiourea in the presence of catalytic amount of hydrochloric acid (HCl)ab initio produced 5-aceto-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine, 1. Later, room temperature Claisen-Schmidt condensation of precursor 1 with diverse aromatic aldehydes which were benzaldehyde derivatives led to the formation of α,β-unsaturated carbonyl side chain, 2a-h. Finally, the thermal annellation through synthetic cyclization furnished crude products which were purified by recrystallization to afford 6-methyl-4-phenyl-5-(substituted-5-phenyl-4H-pyrazol-3-yl)-3,4-dihydropyrimidine-2(1H)-thione derivatives 3a-h in a cheap condition. The chemical structures were authenticated using IR, UV, 1H-NMR and 13C-NMR as well as analytical data. The final products 3a-h possessed good candidature for further investigation regarding their biological activities and pharmacological potential for new drug discovery.
Microwave-assisted approach was utilized as green approach to access a series of 2-propylquinoline-4-carbohydrazide hydrazone derivatives 10a-j of aromatic and heteroaromatic aldehydes in highly ...encouraging yields. It involved four steps reaction which was initiated with ring opening reaction of isatin in a basified environment and subsequent cross-coupling with pentan-2-one to produce compound 7. Esterification of 7 in acid medium led to the formation of compound 8 which was reacted with hydrazine hydrate to access 9 which upon microwave-assisted condensed with aromatic and heteroaromatic aldehydes furnished the targeted compounds 10a-j. The structures of 10a-j were confirmed by physico-chemical, elemental analyses and spectroscopic characterization which include UV, FT-IR, 1H and 13C NMR as well as DEPT-135. The targeted compounds 10a-j, alongside with gentamicin clinical standard, were investigated for their antibacterial efficacies using agar diffusion method. 2-Propyl-N′-(pyridine-3-ylmethylene) quinoline-4-carbohydrazide 10j emerged as the best antibacterial hydrazide-hydrazone with lowest MIC value of 0.39 ± 0.02 – 1.56 ± 0.02 µg/mL across all the organisms screened.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Quinazoline pharmacophore in therapeutic medicine Olayinka Oyewale Ajani; Damilola Victoria Aderohunmu; Ejike Nzube Umeokoro ...
Bangladesh Journal of Pharmacology,
01/2016, Volume:
11, Issue:
3
Journal Article
Peer reviewed
Open access
This present study comprehensively expatiates the functionalized utilization of quinazoline scaffolds in drug development and furnishes latest updates in pharmacological appositeness of its ...derivatives in order to reveal novel pathways for therapeutic targets. It traverses numerous biological potentials of quinazoline in the contemporary time to allow researchers unhindered access to the beneficial role of quinazoline in fighting infectious diseases for future drug discovery. This work provides broad overview of medicinal survey of quinazoline chemistry valuable in the discovery of more efficient clinical trials and to summarize the most promising molecular targets for drug design.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A series of functionalized 2-substituted benzimidazole motifs was designed and successfully synthesized via thermal cyclization of 1,2-diaminobenzene on COOH end of L- leucine to achieve ...benzimidazole derivatives 6 as the essential precursor. The coupling of the precursor 6 with benzaldehyde derivatives a-h, ketone series i-k, and aryl sulfonyl chlorides l-n led to the formation of the targeted 2-substituted benzimidazole motifs 7a-n in improved yields. The targeted benzimidazole motifs were structurally authenticated through their spectral data and microanalytical parameters. The targeted final moieties were investigated for potential antimicrobial activity using the agar diffusion method with gentamicin as the clinical standard. All the compounds had a broad spectrum of activity with compound 7k having the highest remarkable activity with MIC of 0.98 ± 0.02 µg/mL and MBC value of 3.91 ± 0.10 µg/mL. These findings suggest that compound 7k containing camphor might be a good candidate for the design of new antimicrobial small-molecule drugs.
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