Multi-Faceted Antimicrobial Efficacy of a Quinoline-Derived Bidentate Copper(II) Ligand Complex and Its Hydrogel Encapsulated Formulation in Methicillin-Resistant Staphylococcus aureus Inhibition and Wound Management.

The emergence of antimicrobial resistance, exemplified by methicillin-resistant Staphylococcus aureus (MRSA), poses a grave threat to public health globally. Over time, MRSA has evolved resistance to multiple antibiotics, challenging conventional treatment strategies. The relentless adaptability of MRSA underscores the urgent need for innovative and targeted antimicrobial approaches to combat this resilient pathogen. Ancient knowledge and practices, along with scientific evidence, have established that metallic copper, and its organic coordination complexes can act as potential antibacterial substances. In search of a smart and effective antimicrobial against MRSA, we designed, synthesized, and characterized a bidentate copper(II) ligand complex (SG-Cu) utilizing a comprehensive array of analytical techniques, including ESI-MS, elemental analysis, X-ray photoelectron spectroscopy, electron paramagnetic resonance spectroscopy, and others. Antibacterial efficacy and mechanism of action of the complex were assessed through bacterial growth analyses, bacterial membrane perturbation assays, ROS elicitation assays, and field emission scanning electron microscopy. SG-Cu was found to maintain robust biocompatibility against the mammalian cell lines HEK-293, WI-38, and NIH/3T3. Remarkably, SG-Cu demonstrated significant biofilm disruptive tendency evidenced by the retardation of sliding motility, reduction in slime production, reduction in biofilm viability, and enhanced biofilm eradication, both in vitro and in urinary catheters. In vivo studies on murine excisional wounds, with SG-Cu impregnated in a palmitic acid conjugated NAVSIQ hexapeptide (PA-NV) hydrogel, revealed the sustained release of SG-Cu from the gel matrix, facilitating accelerated wound healing and effective wound disinfection. This multifaceted investigation highlights the potential of SG-Cu as a versatile option for combating MRSA infections and promoting wound healing, solidifying its claim to be developed into a viable therapeutic.

Discovery of Quinazoline and Quinoline-Based Small Molecules as Utrophin Upregulators via AhR Antagonism for the Treatment of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease caused by the absence of a dystrophin protein. Elevating utrophin, a dystrophin paralogue, offers an alternative therapeutic strategy for treating DMD, irrespective of the mutation type. Herein, we report the design and synthesis of novel quinazoline and quinoline-based small molecules as potent utrophin modulators screened via high throughput In-Cell ELISA in C2C12 cells. Remarkably, lead molecule SG-02, identified from a library of 70 molecules, upregulates utrophin 2.7-fold at 800 nM in a dose-dependent manner, marking the highest upregulation within the nanomolar range. SG-02's efficacy was further validated through DMD patient-derived cells, demonstrating a significant 2.3-fold utrophin expression. Mechanistically, SG-02 functions as an AhR antagonist, with excellent binding affinity (Kd = 41.68 nM). SG-02 also enhances myogenesis, as indicated by an increased MyHC expression. ADME evaluation supports SG-02's oral bioavailability. Overall, SG-02 holds promise for addressing the global DMD population.

Design, in silico study, synthesis and evaluation of hybrid pyrazole substituted 1,3,5-triazine derivatives for antimalarial activity.

OBJECTIVES: Malaria is a significant global health challenge, particularly in Africa, Asia, and Latin America, necessitating immediate investigation into innovative and efficacious treatments. This work involves the development of pyrazole substituted 1,3,5-triazine derivatives as antimalarial agent. METHODS: In this study, ten compounds 7(a-j) were synthesized by using nucleophilic substitution reaction, screened for in silico study and their antimalarial activity were evaluated against 3D7 (chloroquine-sensitive) strain of P. falciparum. KEY FINDING: The present work involves the development of hybrid trimethoxy pyrazole 1,3,5-triazine derivatives 7 (a-j). Through in silico analysis, four compounds were identified with favorable binding energy and dock scores. The primary focus of the docking investigations was on the examination of hydrogen bonding and the associated interactions with certain amino acid residues, including Arg A122, Ser A108, Ser A111, Ile A164, Asp A54, and Cys A15. The IC50 values of the four compounds were measured in vitro to assess their antimalarial activity against the chloroquine sensitive 3D7 strain of P. falciparum. The IC50 values varied from 25.02 to 54.82 µg/mL. CONCLUSION: Among the ten derivatives, compound 7J has considerable potential as an antimalarial agent, making it a viable contender for further refinement in the realm of pharmaceutical exploration, with the aim of mitigating the global malaria load.

Synergistic Augmentation of Beta-Lactams: Exploring Quinoline-Derived Amphipathic Small Molecules as Antimicrobial Potentiators against Methicillin-Resistant Staphylococcus aureus.

The escalation of bacterial resistance against existing therapeutic antimicrobials has reached a critical peak, leading to the rapid emergence of multidrug-resistant strains. Stringent pathways in novel drug discovery hinder our progress in this survival race. A promising approach to combat emerging antibiotic resistance involves enhancing conventional ineffective antimicrobials using low-toxicity small molecule adjuvants. Recent research interest lies in weak membrane-perturbing agents with unique cyclic hydrophobic components, addressing a significant gap in antimicrobial drug exploration. Our study demonstrates that quinoline-based amphipathic small molecules, SG-B-52 and SG-B-22, significantly reduce MICs of selected beta-lactam antibiotics (ampicillin and amoxicillin) against lethal methicillin-resistant Staphylococcus aureus (MRSA). Mechanistically, membrane perturbation, depolarization, and ROS generation drive cellular lysis and death. These molecules display minimal in vitro and in vivo toxicity, showcased through hemolysis assays, cell cytotoxicity analysis, and studies on albino Wistar rats. SG-B-52 exhibits impressive biofilm-clearing abilities against MRSA biofilms, proposing a strategy to enhance beta-lactam antibiosis and encouraging the development of potent antimicrobial potentiators.

Stepwise reduction of graphene oxide and studies on defect-controlled physical properties.

Graphene oxide (GO) is a monolayer of oxidized graphene which is a convenient and potential candidate in a wide range of fields of applications like electronics, photonics, optoelectronics, energy storage, catalysis, chemical sensors, and many others. GO is often composed of various oxygen-containing groups such as hydroxyl, carboxyl, and epoxy. One appealing method for achieving graphene-like behavior with sp2 hybridized carbon is the reduction of GO i.e. formation of reduced graphene oxide (RGO). A stepwise reduction GO to form a family of RGO, containing various quantities of oxygen-related defects was carried out. Herein, the defects related chemical and physical properties of GO and the RGO family were studied and reported in an effort to understand how the properties of RGO vary with the reduction rate. Although there are several reports on various features and applications of GO and RGO but a systematic investigation of the variation of the physical and chemical properties in RGO with the varying quantities of oxygeneous defects is imperative for the engineered physical properties in achieving the desired field of applications. We have attempted to look at the role of sp2 and sp3 carbon fractions, which are present in RGO-based systems, and how they affect the electrical, optoelectronic, and adsorption characteristics.

Ratiometric Fluorescent Probe Promotes Trans-differentiation of Human Mesenchymal Stem Cells to Neurons.

Development of multifunctional theranostics is challenging and crucial for deciphering complex biological phenomena and subsequently treating critical disease. In particular, development of theranostics for traumatic brain injury (TBI) and understanding its repair mechanism are challenging and highly complex areas of research. Recently, there have been interesting pieces of research work demonstrated that a small molecule-based neuroregenerative approach using stem cells has potential for future therapeutic lead development for TBI. However, these works demonstrated the application of a mixture of multiple molecules as a "chemical cocktail", which may have serious toxic effects in the differentiated cells. Therefore, development of a single-molecule-based potential differentiating agent for human mesenchymal stem cells (hMSCs) into functional neurons is vital for the upcoming neuro-regenerative therapeutics. This lead could be further extraploted for the design of theranostics for TBI. In this study, we have developed a multifunctional single-molecule-based fluorescent probe, which can image the transdifferentiated neurons as well as promote the differentiation process. We demonstrated a promising class of fluorescent probes (CP-4) that can be employed to convert hMSCs into neurons in the presence of fibroblast growth factor (FGF). This fluorescent probe was used in cellular imaging as its fluorescence intensity remained unaltered for up to 7 days of trans-differentiation. We envision that this imaging probe can have an important application in the study of neuropathological and neurodegenerative studies.

A Review on Synthetic Thiazole Derivatives as an Antimalarial Agent.

BACKGROUND: Thiazole is a widely studied core structure in heterocyclic chemistry and has proven to be a valuable scaffold in medicinal chemistry. The presence of thiazole in both naturally occurring and synthetic pharmacologically active compounds demonstrates the adaptability of these derivatives. METHODS: The current study attempted to review and compile the contributions of numerous researchers over the last 20 years to the medicinal importance of these scaffolds, with a primary focus on antimalarial activity. The review is based on an extensive search of PubMed, Google Scholar, Elsevier, and other renowned journal sites for a thorough literature survey involving various research and review articles. RESULTS: A comprehensive review of the antimalarial activity of the thiazole scaffold revealed potential therapeutic targets in Plasmodium species. Furthermore, the correlation of structure-activity-relationship (SAR) studies from various articles suggests that the thiazole ring has therapeutic potential. CONCLUSION: This article intends to point researchers in the right direction for developing potential thiazole-based compounds as antimalarial agents in the future.

Designed novel nuclear localizing anticancer peptide targets p53 negative regulator MDM2 protein.

Intracellular protein-protein interactions provide a major therapeutic target for the development of peptide-based anticancer therapeutic agents. MDM2 is the 491-residue protein encoded by the MDM2 oncogene. Being a ubiquitin-protein ligase, MDM2 represses the transcription ability of the tumor suppressor p53 by proteasome-mediated degradation. Under typical cellular circumstances, a sustained p53 expression level is maintained by negative regulation of MDM2, whereas under stress conditions, this is alleviated to increase the p53 level. Modulation of MDM2-p53 interaction via fabrication of an MDM2-interacting peptide could be a useful strategy to inhibit subsequent proteasomal degradation of p53 and initiation of p53 signaling leading to the initiation of p53-mediated apoptosis of tumor cells. Here, in this research work, a novel anticancer peptide mPNC-NLS targeting the nucleus and the MDM2 protein (p53 negative regulator) was designed to promote the p53 protein activity for the prevention of cancer. It induces effective apoptosis in both A549 and U87 cells and remains non-cytotoxic to normal lung fibroblast cells (WI38). Further, immunocytochemistry and Western blot results confirm that the designed mPNC-NLS peptide induces the apoptotic death of lung cancer cells via activation of p53 and p21 proteins and remarkably stifled the in vitro growth of 3D multicellular spheroids composed of A549 cells.

Molecular mechanism of cognitive impairment associated with Parkinson's disease: A stroke perspective.

Parkinson's disease (PD) is a common neurological illness that causes several motor and non-motor symptoms, most characteristically limb tremors and bradykinesia. PD is a slowly worsening disease that arises due to progressive neurodegeneration of specific areas of the brain, especially the substantia nigra of the midbrain. Even though PD has continuously been linked to a higher mortality risk in numerous epidemiologic studies, there have been significant discoveries regarding the connection between PD and stroke. The incidence of strokes such as cerebral infarction and hemorrhage is substantially associated with the development of PD. Moreover, cognitive impairments, primarily dementia, have been associated with stroke and PD. However, the underlying molecular mechanism of this phenomenon is still obscure. This concise review focuses on the relationship between stroke and PD, emphasizing the molecular mechanism of cognition deficit and memory loss evident in PD and stroke. Furthermore, we are also highlighting some potential drug molecules that can target both PD and stroke.

Photocatalytic degradation of tetracycline antibiotics by RGO-CdTe composite with enhanced apparent quantum efficiency.

RGO-CdTe composite was synthesized using a straightforward, easy-to-realize, one-pot solvothermal technique. The synthesized composite was characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), Brunauer-Emmett-Teller method (BET), Raman spectra, UV-Vis absorption, and photoluminescence measurement. The RGO-CdTe composite exhibited 83.6% photocatalytic degradation efficiency for the aqueous tetracycline (TC) antibiotic solution and the apparent quantum yield (AQY) for the same was as high as 22.29% which is 2.63 times higher than that of CdTe. The scavenger investigation demonstrated that although hole acts as the leading active species, despite that, superoxide and hydroxyl radicals have also played crucial roles. The initial pH-dependent photocatalytic performance was measured. The zeta potential of the composite at different pH values was evaluated to establish the photocatalytic performance of the RGO-CdTe towards TC degradation at different pH. The recycling experiment depicts that only a 10% degradation performance declines after 5 times recycle use of the RGO-CdTe photocatalyst. An efficient photocurrent generation in RGO-CdTe thin film device has also been observed. Our study establishes as-synthesized composite of RGO-CdTe as a highly potential, and stable photocatalyst for the degradation of antibiotics from the polluted aqueous environment with a very good photoinduced charge generation efficiency in its solid phase.

Hybrid PABA-glutamic acid conjugated 1,3,5-triazine derivatives: Design, synthesis, and antimalarial activity screening targeting Plasmodium falciparum dihydro folate reductase enzyme.

Despite the successful reduction in the malaria health burden in recent years, it continues to remain a significant global health problem mainly because of the emerging resistance to first-line treatments. Also because of the disruption in malaria prevention services during the COVID-19 pandemic, there was an increase in malaria cases in 2021 compared to 2020. Hence, the present study outlined the in silico study, synthesis, and antimalarial evaluation of 1,3,5-triazine hybrids conjugated with PABA-glutamic acid. Docking study revealed higher binding energy compared to the originally bound ligand WR99210, predominant hydrogen bond interaction, and involvement of key amino acid residues, like Arg122, Ser120, and Arg59. Fourteen compounds were synthesized using traditional and microwave synthesis. The in vitro antimalarial evaluation against chloroquine-sensitive 3D7 and resistant Dd2 strain of Plasmodium falciparum showed a high to moderate activity range. Compounds C1 and B4 showed high efficacy against both strains and a further study revealed that compound C1 is non-cytotoxic against the HEK293 cell line with no acute oral toxicity. In vivo, study was performed for the most potent antimalarial compound C1 to optimize the research work and found to be effectively suppressing parasitemia of Plasmodium berghei strain in the Swiss albino mice model.

Ebselen: A Review on its Synthesis, Derivatives, Anticancer Efficacy and Utility in Combating SARS-COV-2.

Ebselen is a selenoorganic chiral compound with antioxidant properties comparable to glutathione peroxidase. It is also known as 2-phenyl-1,2-benzisoselenazol-3(2H)-one. In studies examining its numerous pharmacological activities, including antioxidant, anticancer, antiviral, and anti-Alzheimer's, ebselen has demonstrated promising results. This review's primary objective was to emphasize the numerous synthesis pathways of ebselen and their efficacy in fighting cancer. The data were collected from multiple sources, including Scopus, PubMed, Google Scholar, Web of Science, and Publons. The starting reagents for the synthesis of ebselen are 2-aminobenzoic acid and N-phenyl benzamide. It was discovered that ebselen has the ability to initiate apoptosis in malignant cells and prevent the formation of new cancer cells by scavenging free radicals. In addition, ebselen increases tumor cell susceptibility to apoptosis by inhibiting TNF-α mediated NF-jB activation. Ebselen can inhibit both doxorubicin and daunorubicin-induced cardiotoxicity. Allopurinol and ebselen administered orally can be used to suppress renal ototoxicity and nephrotoxicity. Due to excessive administration, diclofenac can induce malignancy of the gastrointestinal tract, which ebselen can effectively suppress. Recent research has demonstrated ebselen to inhibit viral function by binding to cysteine-containing catalytic domains of various viral proteases. It was discovered that ebselen could inhibit the catalytic dyad function of Mpro by forming an irreversible covalent bond between Se and Cys145, thereby altering protease function and inhibiting SARS-CoV-2. Ebselen may also inhibit the activation of endosomal NADPH oxidase of vascular endothelial cells, which is believed to be required for thrombotic complications in COVID-19. In this review, we have included various studies conducted on the anticancer effect of ebselen as well as its inhibition of SARS-CoV-2.

Potential Broad-Spectrum Antimicrobial, Wound Healing, and Disinfectant Cationic Peptide Crafted from Snake Venom.

Antimicrobial cationic peptides are intriguing and propitious antibiotics for the future, even against multidrug-resistant superbugs. Venoms serve as a source of cutting-edge therapeutics and innovative, unexplored medicines. In this study, a novel cationic peptide library consisting of seven sequences was designed and synthesized from the snake venom cathelicidin, batroxicidin (BatxC), with the inclusion of the FLPII motif at the N-terminus. SP1V3_1 demonstrated exceptional antibacterial effectiveness against Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae and destroyed the bacteria by depolarizing, rupturing, and permeabilizing their membranes, as evident from fluorescence assays, atomic force microscopy, and scanning electron microscopy. SP1V3_1 was observed to modulate the immune response in LPS-elicited U937 cells and exhibited good antibiofilm activity against MRSA and K. pneumoniae. The peptide promoted wound healing and disinfection in the murine model. The study demonstrated that SP1V3_1 is an exciting peptide lead and may be explored further for the development of better therapeutic peptides.

The Role of Protein-L-isoaspartyl Methyltransferase (PIMT) in the Suppression of Toxicity of the Oligomeric Form of Aß42, in Addition to the Inhibition of Its Fibrillization.

The oligomeric form of amyloid-ß peptide (Aß42) plays a crucial role in the pathogenesis of Alzheimer's disease (AD) and is responsible for cognitive deficits. The soluble oligomers are believed to be more toxic compared to the fibril form. Protein-L-isoaspartyl methyltransferase (PIMT) is a repair enzyme that converts aberrant isoAsp residues, formed spontaneously on isomerization of normal Asp and Asn residues, back to typical Asp. It was shown to inhibit the fibrillization of Aß42 (containing three Asp residues), and here, we investigate its effect on the size, conformation, and toxicity of Aß42 oligomers (AßO). Far-UV CD indicated a shift in the conformational feature of AßOs from the random coil to ß-sheet in the presence of PIMT. Binding of bis-ANS to different AßOs (obtained using different concentrations of Aß42 monomer) indicated the correlation of size of oligomers to hydrophobicity: the smallest AßO having the highest hydrophobicity is the most toxic. Dynamic light scattering showed an increase in size of AßO with the addition of PIMT, a contrasting role to that on Aß fibril. Assays using PC12-derived neurons showed the neuroprotective role of PIMT against AßO-induced toxicity. Furthermore, we have elaborated on the molecular mechanism of the antifibrillar action of PIMT and how this function is correlated with its enzymatic activity. PIMT has a more pronounced effect on AßO as compared to a small heat shock protein, pointing to its importance for the amelioration of the adverse effect of both Aß42 oligomers and fibrils.

Invasion potential of the aquarium pet snail Planorbella trivolvis in India: impact of certain abiotic and biotic factors.

Planorbella trivolvis (ramshorn snail) is one of India's most extensively sold exotic aquarium pet snails. The unintentional or deliberate release of P. trivolvis may result in the colonisation and establishment as an invasive snail in freshwater ecosystems. However, the successful invasion of P. trivolvis will depend on several abiotic and biotic factors of the concerned freshwater ecosystem. We have assessed the possibility of overcoming the opposing factors in P. trivolvis invasion through laboratory-based experiments and examined the effects of household-derived pollutants on egg hatchability, adult survivability and fecundity, and temperature (15 to 35 °C) on growth, sexual maturity, and reproduction. Additionally, we have evaluated the potential of native predators as biotic resistance to invasion by prey-choice experiment. The results indicated that egg hatchability, adult survivability, and fecundity were reduced with increasing pollutant concentration. However, the same traits did not differ from a native freshwater snail, Indoplanorbis exustus. The fecundity of P. trivolvis increased with increasing body size, but no considerable differences at different temperature levels suggest a wide range of adaptation to temperature. Faster growth and the requirement of comparatively few days to attain sexual maturity were observed in the higher temperatures. The native predators, Glossiphonia weberi and Diplonychus rusticus, avoided P. trivolvis as prey over the alternative prey snails in most instances, suggesting the masking of biotic resistance against the colonisation. Our observations indicate that the chance dispersal of P. trivolvis from household or commercial aquaria may lead to a possible invasion of freshwater ecosystems under suitable conditions.

Amyloid-Inspired Engineered Multidomain Amphiphilic Injectable Peptide Hydrogel─An Excellent Antibacterial, Angiogenic, and Biocompatible Wound Healing Material.

The ingrained mechanical robustness of amyloids in association with their fine-tunable physicochemical properties results in the rational design and synthesis of tailor-made biomaterials for specific applications. However, the incredible antimicrobial efficacy of these ensembles has largely been overlooked. This research work provides an insight into the interplay between self-assembly and antimicrobial activity of amyloid-derived peptide amphiphiles and thereby establishes a newfangled design principle toward the development of potent antimicrobial materials with superior wound healing efficacy. Apart from the relationship with many neurodegenerative diseases, amyloids are now considered as an important cornerstone of our innate immune response against pathogenic microbes. Impelled by this observation, a class of amphiphilic antimicrobial peptide-based biomaterial has been designed by taking Aß42 as a template. The designed AMP due to its amphipathic nature undergoes rapid self-assembly to form a biocompatible supramolecular hydrogel network having significant antibacterial as well as wound healing effectivity on both Gram-negative P. aeruginosa and MRSA-infected diabetic wounds via reduced inflammatory response and enhanced angiogenesis. Results suggest that disease-forming amyloids can be used as a blueprint for the fabrication of biomaterial-based antimicrobial therapeutics by fine-tuning both the hydrophobicity of the ß-aggregation prone zone as well as membrane interacting cationic residues.

Substance P-Derived Extracellular-Matrix-Mimicking Peptide Hydrogel as a Cytocompatible Biomaterial Platform.

Self-assembled short peptide-based hydrogel platforms have become widely applicable biomedical therapeutic maneuvers for their soft, tunable architecture, which can influence cellular behavior and morphology to an inordinate extent. In this work, a short supramolecular hydrogelator peptide, substance P, has been designed and synthesized from the C terminus conserved "FFGLM" section of a biologically abundant neuropeptide by using a fusion approach. In addition, to incorporate a good hydrophobic-hydrophilic balance, the truncated pentapeptide segment was further C-terminally modified by the incorporation of an integrin-binding "RGD" motif. Thanks to its N-terminal Fmoc group, this octapeptide ensemble "FFGLMRGD" undergoes rapid self-assembly to give rise to an injectable, pH-responsive, hydrogel-based self-supporting platform that exhibited good cytocompatibility with the cultured mammalian cells under both 2D and 3D culture conditions without exerting any potent cytotoxic effect in a Live/Dead experiment. A rheological experiment demonstrated its hydrogel-like mechanical properties, including thixotropicity. The atomic force microscopy and field emission scanning electron microscopy images of the fabricated hydrogel show a tangled fibrous surface topography owing to the presence of the N-terminal Fmoc-FF residue. Furthermore, an in-vitro scratch assay performed on fibroblast cell lines confirmed the wound-ameliorating potency of this designed hydrogel; this substantiates its future therapeutic prospects.

Monitoring tea plantations during 1990-2022 using multi-temporal satellite data in Assam (India).

Background: Tea is a valuable economic plant grown extensively in several Asian countries. The accurate mapping of tea plantations is critical for the growth and development of the tea industry. In eastern India, tea plantations have a significant role in its economy. Sonitpur, Jorhat, Sibsagar, Dibrugarh, and Tinsukia are major tea-producing districts in Assam. Due to the rapid increase in tea plantations and the burgeoning population, a detailed mapping and regular monitoring of tea plantations are imperative for understanding land use alteration. Objectives: The present study aims to analyse the dynamics of tea plantations from 1990 to 2022 at a decadal scale, using satellite data, such as Landsat-5 and Sentinel-2. Methods: A supervised classifier called Random Forest (RF) was deployed in the Google Earth Engine (GEE) platform to classify tea plantations. Results: The results showed significant growth in tea plantations in the district of Dibrugarh (112%), whereas the remaining districts had a growth rate of 45-89%. During 32 years (1990-2022), about 1280.47 km2 (78.71%) of areas of tea plantations expanded across five districts of Assam. Precision and recall were used to measure the accuracy of tea plantations classification, which exhibited considerably high F1 scores (0.80 to 0.96). Conclusions: This study helps to demonstrate the application of remote sensing techniques to evaluate the dynamics of tea plantations which can help policymakers to manage the tea estates and underlying changes in land cover.

Molecular docking and antimalarial evaluation of hybrid para-aminobenzoic acid 1,3,5 triazine derivatives via inhibition of Pf-DHFR.

In this study, a structurally guided pharmacophore hybridization strategy is used to combine the two key structural scaffolds, para-aminobenzoic acid (PABA), and 1,3,5 triazine in search of new series of antimalarial agents. A combinatorial library of 100 compounds was prepared in five different series as [4A (1-22), 4B (1-21), 4 C (1-20), 4D (1-19) and 4E (1-18)] using different primary and secondary amines, from where 10 compounds were finally screened out through molecular property filter analysis and molecular docking study as promising PABA substituted 1,3,5-triazine scaffold as an antimalarial agent. The docking results showed that compounds 4A12 and 4A20 exhibited good binding interaction with Phe58, IIe164, Ser111, Arg122, Asp54 (-424.19 to -360.34 kcal/mol) and Arg122, Phe116, Ser111, Phe58 (-506.29 to -431.75 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR. These compounds were synthesized by conventional as well as microwave-assisted synthesis and characterized by different spectroscopic methods. In-vitro antimalarial activity results indicated that two compounds 4A12 and 4A20 showed promising antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of Plasmodium falciparum with IC50 (1.24-4.77 µg mL-1) and (2.11-3.60 µg mL-1). These hybrid PABA substituted 1,3,5-triazine derivatives might be used in the lead discovery towards a new class of Pf-DHFR inhibitors.Communicated by Ramaswamy H. Sarma.