Sulfonamide based pyrimidine derivatives combating parasite by inhibiting falcipains-2 and falcipains-3 as antimalarial agents.

In this report, we present the design and synthesis of a novel series of pyrimidine-tethered spirochromane-based sulfonamide derivatives aimed at combating drug resistance in malaria. The antimalarial effectiveness of these compounds was assessed . Structural validation of the synthesized compounds was conducted using mass spectrometry and NMR spectroscopy.

Robust leishmanicidal upshot of some new diphenyl triazine-based molecules.

Amongst the neglected tropical diseases, leishmaniasis alone causes 30 000 deaths annually due to the protozoan parasite genus . Existing therapies have serious drawbacks in safety, drug resistance, field-adapted application and cost. Therefore, new safer and shorter treatments are an urgent need of the time.

Discovery of Quinolinone Hybrids as Dual Inhibitors of Acetylcholinesterase and Aβ Aggregation for Alzheimer's Disease Therapy.

The development of multitargeted therapeutics has evolved as a promising strategy to identify efficient therapeutics for neurological disorders. We report herein new quinolinone hybrids as dual inhibitors of acetylcholinesterase (AChE) and Aβ aggregation that function as multitargeted ligands for Alzheimer's disease. The quinoline hybrids (- were screened for their ability to inhibit AChE, BACE1, amyloid fibrillation, α-syn aggregation, and tau aggregation.

Naphthyl bearing 1,3,4-thiadiazoleacetamides targeting the parasitic folate pathway as anti-infectious agents: , synthesis, and biological approach.

Malaria is still a complex and lethal parasitic infectious disease, despite the availability of effective antimalarial drugs. Resistance of malaria parasites to current treatments necessitates new antimalarials targeting proteins. The present study reported the design and synthesis of a series of a 2-(4-substituted piperazin-1-yl)--(5-((naphthalen-2-yloxy)methyl)-1,3,4-thiadiazol-2-yl)acetamide hybrids for the inhibition of dihydrofolate reductase (DHFR) using computational biology tools followed by chemical synthesis, structural characterization, and functional analysis.

identification of colchicine derivatives as novel and potential inhibitors based on molecular docking and dynamic simulations targeting multifactorial drug targets involved in Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by a gradual and steady deterioration in cognitive function over time. At least 50 million people worldwide are considered to have AD or another form of dementia. AD is marked by a gradual decline in cognitive abilities, memory deterioration and neurodegenerative transformations within the brain.

Design, synthesis, and biological evaluation of morpholinopyrimidine derivatives as anti-inflammatory agents.

Here, we outline the synthesis of a few 2-methoxy-6-((4-(6-morpholinopyrimidin-4-yl)piperazin-1-yl)(phenyl)methyl)phenol derivatives and assess their anti-inflammatory activity in macrophage cells that have been stimulated by LPS. Among these newly synthesized morpholinopyrimidine derivatives, 2-methoxy-6-((4-methoxyphenyl)(4-(6-morpholinopyrimidin-4-yl)piperazin-1-yl)methyl)phenol (V4) and 2-((4-fluorophenyl)(4-(6-morpholinopyrimidin-4-yl)piperazin-1-yl)methyl)-6-methoxyphenol (V8) are two of the most active compounds which can inhibit the production of NO at non-cytotoxic concentrations. Our findings also showed that compounds V4 and V8 dramatically reduced iNOS and cyclooxygenase mRNA expression (COX-2) in LPS-stimulated RAW 264.

Development of diphenylmethylpiperazine hybrids of chloroquinoline and triazolopyrimidine using Petasis reaction as new cysteine proteases inhibitors for malaria therapeutics.

Malaria is a widespread infectious disease, causing nearly 247 million cases in 2021. The absence of a broadly effective vaccine and rapidly decreasing effectiveness of most of the currently used antimalarials are the major challenges to malaria eradication efforts. To design and develop novel antimalarials, we synthesized a series of 4,7-dichloroquinoline and methyltriazolopyrimidine analogues using a multi-component Petasis reaction.

Multicomponent Petasis reaction for the identification of pyrazine based multi-target directed anti-Alzheimer's agents: In-silico design, synthesis, and characterization.

Multi-target directed ligands (MTDLs) have recently attracted significant interest due to their exceptional effectiveness against multi-factorial Alzheimer's disease. The present work described the development of pyrazine-based MTDLs using multicomponent Petasis reaction for the dual inhibition of tau-aggregation and human acetylcholinesterase (hAChE). The molecular structure of synthesized ligands was validated by H & C NMR and mass spectrometry.

Identification of new oxospiro chromane quinoline-carboxylate antimalarials that arrest parasite growth at ring stage.

Malaria still threatens half the globe population despite successful Artemisinin-based combination therapy. One of the reasons for our inability to eradicate malaria is the emergence of resistance to current antimalarials. Thus, there is a need to develop new antimalarials targeting proteins.

Identification, in-vitro anti-plasmodial assessment and docking studies of series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide molecular hybrids as potential antimalarial agents.

Malaria is the most lethal parasitic infections in the world. To address the emergence of drug resistance to current antimalarials, here we report the design and synthesis of new series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide hybrids by using multicomponent Petasis reaction as the key step and evaluated in vitro for their antimalarial effectiveness. The structure of all the compounds were confirmed by NMR Spectroscopy and mass spectrometry.

Synthesis and Pharmacological Evaluation of Novel Triazole-Pyrimidine Hybrids as Potential Neuroprotective and Anti-neuroinflammatory Agents.

Objective: Neuroprotection is a precise target for the treatment of neurodegenerative diseases, ischemic stroke, and traumatic brain injury. Pyrimidine and its derivatives have been proven to use antiviral, anticancer, antioxidant, and antimicrobial activity prompting us to study the neuroprotection and anti-inflammatory activity of the triazole-pyrimidine hybrid on human microglia and neuronal cell model.

Methods: A series of novel triazole-pyrimidine-based compounds were designed, synthesized and characterized by mass spectra, 1HNMR, 13CNMR, and a single X-Ray diffraction analysis.

Development of benzene and benzothiazole-sulfonamide analogues as selective inhibitors of the tumor-associated carbonic anhydrase IX.

With an aim to develop novel potential antitumor agents, two series of benzene- and benzothiazole-sulfonamide derivatives, acting as effective human carbonic anhydrase (hCA, EC 4.2.1.

Recent advancements in chromone as a privileged scaffold towards the development of small molecules for neurodegenerative therapeutics.

Neurodegenerative disorders, , Alzheimer's or Parkinson's disease, involve progressive degeneration of the central nervous system, resulting in memory loss and cognitive impairment. The intensification of neurodegenerative research in recent years put some molecules into clinical trials, but still there is an urgent need to develop effective therapeutic molecules to combat these diseases. Chromone is a well-identified privileged structure for the design of well-diversified therapeutic molecules of potential pharmacological interest, particularly in the field of neurodegeneration.

Dual targeting of acetylcholinesterase and tau aggregation: Design, synthesis and evaluation of multifunctional deoxyvasicinone analogues for Alzheimer's disease.

Development of multitargeted ligands have demonstrated remarkable efficiency as potential therapeutics for Alzheimer's disease (AD). Herein, we reported a new series of deoxyvasicinone analogues as dual inhibitor of acetylcholinesterase (AChE) and tau aggregation that function as multitargeted ligands for AD. All the multitargeted ligands 11(a-j) and 15(a-g) were designed, synthesized, and validated by HNMR, CNMR and mass spectrometry.

Novel triazole-sulfonamide bearing pyrimidine moieties with carbonic anhydrase inhibitory action: Design, synthesis, computational and enzyme inhibition studies.

A series of new triazole-sulfonamide bearing pyrimidine derivatives were designed and synthesized via click chemistry. All new compounds (SH-1 to SH-28) were validated by HNMR, CNMR, HRMS, and SH-3 was further structurally validated by X-Ray single diffraction study. These compounds (SH-1 to SH-28) were tested as inhibitors of human carbonic anhydrase (hCA) isoforms, such as hCA I, II, IX and XII, using a stopped flow CO hydrase assay.

Design, synthesis, crystal structure and anti-plasmodial evaluation of tetrahydrobenzo[4,5]thieno[2,3-]pyrimidine derivatives.

Effective chemotherapy is essential for controlling malaria. However, resistance of to existing antimalarial drugs has undermined attempts to control and eventually eradicate the disease. In this study, a series of 2-((substituted)(4-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-]pyrimidin-4-yl)piperazin-1-yl)methyl)-6-substitutedphenol derivatives were prepared using Petasis reaction with a view to evaluate their activities against .

Discovery of new phenyl sulfonyl-pyrimidine carboxylate derivatives as the potential multi-target drugs with effective anti-Alzheimer's action: Design, synthesis, crystal structure and in-vitro biological evaluation.

Alzheimer's disease (AD) is multifactorial, progressive neurodegeneration with impaired behavioural and cognitive functions. The multitarget-directed ligand (MTDL) strategies are promising paradigm in drug development, potentially leading to new possible therapy options for complex AD. Herein, a series of novel MTDLs phenylsulfonyl-pyrimidine carboxylate (BS-1 to BS-24) derivatives were designed and synthesized for AD treatment.

Unravelling the potency of triazole analogues for inhibiting α-synuclein fibrillogenesis and disaggregation.

A series of triazole-based compounds was synthesized using a click chemistry approach and evaluated for the inhibition of α-synuclein (α-syn) fibrillogenesis and its disaggregation. Compounds Tr3, Tr7, Tr12, Tr15, and Tr16 exhibited good effect in inhibiting α-syn fibrillogenesis confirmed by Thioflavin-T assay and fluorescence microscopy and α-syn disaggregation confirmed by fluorescence microscopy. Molecular docking was used to understand the plausible mechanism of the test compounds for inhibiting the α-syn fibrillogenesis and to verify the in vitro results.

Quinoline carboxamide core moiety-based compounds inhibit P. falciparumfalcipain-2: Design, synthesis and antimalarial efficacy studies.

Targeting Falcipain-2 (FP2) for the development of antimalarials is a promising and established concept in antimalarial drug discovery and development. FP2, a member of papain-family cysteine protease of the malaria parasite Plasmodium falciparum holds an important role in hemoglobin degradation pathway. A new series of quinoline carboxamide-based compounds was designed, synthesized and evaluated for antimalarial activity.

An insight into the recent development of the clinical candidates for the treatment of malaria and their target proteins.

Malaria is an endemic disease, prevalent in tropical and subtropical regions which cost half of million deaths annually. The eradication of malaria is one of the global health priority nevertheless, current therapeutic efforts seem to be insufficient due to the emergence of drug resistance towards most of the available drugs, even first-line treatment ACT, unavailability of the vaccine, and lack of drugs with a new mechanism of action. Intensification of antimalarial research in recent years has resulted into the development of single dose multistage therapeutic agents which has advantage of overcoming the antimalarial drug resistance.

Diphenyl triazine hybrids inhibit α-synuclein fibrillogenesis: Design, synthesis and in vitro efficacy studies.

Aggregation of α-synuclein (α-syn) is one of the central hypotheses for Parkinson's disease (PD), therefore, its inhibition and disaggregation is an optimistic approach for the treatment of PD. Here, we report design, synthesis and in-vitro efficacy studies of a series of diphenyl triazine hybrids as potential inhibitors of α-syn fibrillogenesis. From the docking studies, we concluded that compounds A1, A2, A4, A8 and A9 display promising binding affinity with the essential residues of α-syn with binding energy values: -6.

A comprehensive review of monoamine oxidase inhibitors as Anti-Alzheimer's disease agents: A review.

Monoamine oxidases (MAO-A and MAO-B) are mammalian flavoenzyme, which catalyze the oxidative deamination of several neurotransmitters like norepinephrine, dopamine, tyramine, serotonin, and some other amines. The oxidative deamination produces several harmful side products like ammonia, peroxides, and aldehydes during the biochemical reaction. The concentration of biochemical neurotransmitter alteration in the brain by MAO is directly related with several neurological disorders like Alzheimer's disease and Parkinson's disease (PD).

Deciphering the robustness of pyrazolo-pyridine carboxylate core structure-based compounds for inhibiting α-synuclein in transgenic C. elegans model of Synucleinopathy.

Parkinson's disease (PD), a calamitous neurodegenerative disorder with no cure till date, is closely allied with the misfolding and aggregation of α-Synuclein (α -Syn). Inhibition of α-Syn aggregation is one of the optimistic approaches for the treatment for PD. Here, we carried out hypothesis-driven studies towards synthesising a series of pyrazolo-pyridine carboxylate containing compounds (7a-7m) targeted at reducing deleterious α-Syn aggregation.

Quinoline-triazole hybrids inhibit falcipain-2 and arrest the development of at the trophozoite stage.

Falcipain-2 (FP2) is a papain family cysteine protease and a key member of the hemoglobin degradation pathway, a process that is required at erythrocytic stages of to obtain amino acids. In this study, we report a set of 10 quinoline-triazole-based compounds (T1-T10) which exhibit a good binding affinity for FP2, inhibit its catalytic activity at micromolar concentrations and thereby arrest the parasite growth. Compounds T4 and T7 inhibited FP2 with IC values of 16.