Pharmacophoric Moieties Research Articles

Exploiting Enantiopure β‐Amino Boronic Acids in Isocyanide‐Based Multicomponent Reactions

AbstractVarious isocyanide‐based multicomponent reactions prove to be highly reliable when β‐substituted β‐amino boronic esters are employed as the amine component, allowing the efficient synthesis of unprecedented peptidomimetics and heteroatom‐rich boron‐containing small molecules. In particular, the scope of the Ugi reaction is widely exploited, to give a family of enantiopure β‐substituted β‐amido boronates. The Ugi‐azide and the van Leusen reactions allow to joint together prominent pharmacophoric moieties, such as β‐amino boronic acids on one side, and tetrazole or imidazole rings on the other side, realizing a successful application of the molecular hybridization concept.

To Synthesize Naphthalene Derivatives Having Isoxazole Central Core as Anti- Microbial Agents

The presence of heterocycles such as pyrrole, thiazole, oxazole, furane, imidazole, and isoxazole and pyrimidine nucleus as central scaffold is a common feature in the chemical structure of several antimicrobial agents. So the aim has been designed to synthesize the molecule having Naphthalene ring in one of diaryl having isoxazole as pharmacophoric heterocyclic moiety for synthesis of safer anti-microbial agents. Keywords: Naphthalene, isoxazole, anti-microbial agents.

Design, synthesis and bioevaluation of new vanillin hybrid as multitarget inhibitor of α-glucosidase, α-amylase, PTP-1B and DPP4 for the treatment of type-II diabetes.

Diabetes mellitus (DM) is a real challenge to the recent era and is one of the major diseases for initiating life-threatening disorders. In current research, a compound was designed by combining vanillin, thiazolidinedione and morpholine. The goal of our designed work is to demonstrate the ability of our design compound (9) to modulate more than one target responsible for hyperglycemia at the same time. The synthesized compound was able to show good to moderate inhibition potential against α-glucosidase, α-amylase and protein tyrosine phosphatase 1B. However, it exhibited excellent in-vitro inhibition of Dipeptidyl peptidase-4 (DPP-4) with IC50 value of 0.09µM. Antioxidant activity by using DPPH assay also showed its good antioxidant potential. In in-vivo experiments, the compound 9 was proved to be safe in experimental mice. The activity profile of the compound was observed for 21 days which showed that the compound was also effective in experimental mice. Binding orientations and Interactions with key amino acid residues of the selected targets were also studied by using docking studies. Overall, we were successful in synthesizing multitarget preclinical therapeutic by combining three pharmacophoric moieties into a single chemical entity that can modulate more than one target at the same time.

Inside the cracked kernel: establishing the molecular basis of AMG510 and MRTX849 in destabilising KRASG12C mutant switch I and II in cancer treatment

The Kirsten rat sarcoma oncoprotein (KRAS) has been punctuated by drug development failures for decades due to frequent mutations that occur mostly at codon 12 and the seemingly intractable targeting of the protein. However, with advances in covalent targeting, the oncoprotein is being expunged from the ‘undruggable’ list of proteins. This feat has seen some covalent drugs at different stages of clinical trials. The advancement of AMG510 and MRTX849 as inhibitors of cysteine mutated KRAS (KRASG12C) to phase-III clinical trials informed the biased selection of AMG510 and MRTX849 for this study. Despite this advance, the molecular and atomistic modus operandi of these drugs is yet to come to light. In this study, we employed computational tools to unravel the atomistic interactions and subsequent conformational effects of AMG510 and MRTX849 on the mutant KRASG12C. It was revealed that AMG510 and MRTX849 complexes presented similar total free binding energies, (ΔG bind), of –88.15 ± 5.96 kcal/mol and –88.71 ± 7.70 kcal/mol, respectively. Gly10, Lys16, Thr58, Gly60, Glu62, Glu63, Arg68, Asp69, Met72, His95, Tyr96, Gln99, Arg102 and Val103 interacted prominently with AMG510 and MRTX849. These residues interacted with the pharmacophoric moieties of AMG510 and MRTX849 via hydrogen bonds with decreasing bond lengths at various stages of the simulation. These interactions together with pi-pi stacking, pi-sigma and pi-alkyl interactions induced unfolding of switch I whiles compacting switch II, which could interrupt the binding of effector proteins to these interfaces. These insights present useful atomistic perspectives into the success of AMG510 and MRTX849 which could guide the design of more selective and potent KRAS inhibitors. Communicated by Ramaswamy H. Sarma

New 1,3,4-oxadiazoles linked with the 1,2,3-triazole moiety as antiproliferative agents targeting the EGFR tyrosine kinase.

A series of 1,3,4-oxadiazole-1,2,3-triazole hybrids bearing different pharmacophoric moieties has been designed and synthesized. Their antiproliferative activity was evaluated against four human cancer cell lines (Panc-1, MCF-7, HT-29, and A-549) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The preliminary activity test displayed that the most active compounds, 6d, 6e, and 8a-e, suppressed cancer cell growth (GI50 = 0.23-2.00 µM) comparably to erlotinib (GI50 = 0.06 µM). Compounds 6d, 6e, and 8a-e inhibited the epidermal growth factor receptor tyrosine kinase (EGFR-TK) at IC50 = 0.11-0.73 µM, compared to erlotinib (IC50 = 0.08 ± 0.04 µM). The apoptotic mechanism revealed that the most active hybrid 8d induced expression levels of caspase-3, caspase-9, and cytochrome-c in the human cancer cell line Panc-1 by 7.80-, 19.30-, and 13-fold higher than doxorubicin. Also, 8d increased the Bax level by 40-fold than doxorubicin, along with decreasing Bcl-2 levels by 6.3-fold. Cell cycle analysis after treatment of Panc-1 cells with hybrid 8d revealed a high proportion of cell accumulation (41.53%) in the pre-G1 phase, indicating cell cycle arrest at the G1 transition. Computational docking of the 8d and 8e hybrids with the EGFR binding site revealed their ability to bind with EGFR similar to erlotinib. Finally, in silico absorption, distribution, metabolism, and excretion/pharmacokinetic studies for the most active hybrids are discussed.

Disrupting the characteristic twist motion; tailored in silico approach towards the design of plasmepsin inhibitors

The effort to eradicate malaria has not yet been achieved, and the parasitic infection remains a global challenge. The burden stems from the worldwide dissemination of parasites resistant to commonly used chemotherapeutics and the scarcity of the malaria vaccine, Mosquirix. In the quest to augment malaria treatment, current focus has been geared towards plasmepsin (P). These classes of aspartic acid proteases are expressed at multiple stages of the parasite's life cycle and are implicated in host haemoglobin degradation and parasite dissemination in vivo; elaborating their essentiality as therapeutic targets. Our earlier research examined the structural dynamics of WM382, a novel antimalarial compound, in relation to its enzyme inhibitory mechanism on plasmepsin IX (PMIX) and plasmepsin X (PMX). WM382 inflicts structural compactness on both proteases. The pharmacophoric moieties of WM382 were used in the present study to search the Zinc database for WM382 derivatives. The leads, ZINC06868602, ZINC09431717 and ZINC13367223 formed strong intermolecular bonds with the catalytic dyad Asp32 and Asp281. The flap regions generally move away from the binding pocket, divulging the active site to the inhibitor and keeping it near to the catalytic dyad. However, upon binding of the leads, the flap residues wrapped inward to surround the inhibitors, further restricting the characteristic twist motion of these proteases for enzyme activity. Likewise, for the experimental drug candidate WM382, the identified leads displayed high affinity for PMIX, with total binding free energies of leads estimated to be −33.45 kcal/mol, −30.33 kcal/mol and −29.67 kcal/mol, respectively. Evaluation of per residue energy composition indicated the catalytic dyad contributes immensely towards ligand binding. Results from our study suggest these compounds have better inhibitory prowess against PMIX. The potency of these chemicals should further be tested in the experimental laboratory to evaluate their usefulness.

Improved Synthesis of D‐Isoglutamine: Rapid Access to Desmuramyl Analogues of Muramyl Dipeptide for the Activation of Intracellular NOD2 Receptor and Vaccine Adjuvant Applications

AbstractMuramyl dipeptide (MDP) – the smallest immunomodulatory unit of bacterial peptidoglycan – has adjuvant activity and triggers the innate immune system against bacterial and viral infections. The inherited drawbacks of MDP, such as pyrogenicity and poor macrophage penetration, can be resolved by structural modifications, thereby improving its pharmacological profile and adjuvant activity. Herein, several desmuramyl analogues of MDP were designed by replacing the carbohydrate fragment (MurNAc) of the parent molecule with an immunomodulatory xanthine scaffold. The L−D configurations of the pharmacophoric dipeptidyl moiety were conserved and alkyl chains of moderate length were introduced at isoglutamine to enhance their cellular uptake. The synthesis of these analogues features a novel synthetic route for D‐isoglutamine fragment with an overall yield of >50 % in ten to eleven steps. This sufficiently flexible approach provides rapid access to desmuramyl analogues of MDP on a gram scale, which can help accelerate the development of novel NOD2 agonists and immunoadjuvants.

Heat Shock Proteins HSPA1 and HSP90AA1 Are Upregulated in Colorectal Polyps and Can Be Targeted in Cancer Cells by Anti-Inflammatory Oxicams with Arylpiperazine Pharmacophore and Benzoyl Moiety Substitutions at Thiazine Ring.

Heat shock proteins HSPA1/Hsp70α and HSP90AA1/Hsp90α are crucial for cancer growth but their expression pattern in colorectal polyps or whether they can be modulated by oxicams is unknown. We quantified (RTqPCR) HSPA1 and HSP90AA1 expression in 50 polyp-normal pairs in relation to polyp malignancy potential and examined the effect of piroxicam, meloxicam and five novel analogues on HSPA1 and HSP90AA1 expression (mRNA/protein) in colorectal adenocarcinoma lines. HSPA1 and HSP90AA1 were upregulated in polyps by 3- and 2.9-fold. Expression ratios were higher in polyps with higher dysplasia grade and dominant villous growth pattern, mostly a result of diminished gene expression in normal tissue. Classic oxicams had negligible/non-significant effect on HSP expression. Their most effective analogue inhibited HSPA1 protein and gene by 2.5-fold and 5.7-fold in Caco-2 and by 11.5-fold and 6.8-fold in HCT116 and HSPA1 protein in HT-29 by 1.9-fold. It downregulated HSP90AA1 protein and gene by 1.9-fold and 3.7-fold in Caco-2 and by 2-fold and 5.0-fold in HCT116. HSPA1 and HSP90AA1 are upregulated in colorectal polyps reflecting their potential for malignancy. HSPA1 in cancer cells and, to lesser degree, HSP90AA1 can be reduced by oxicam analogues with thiazine ring substituted via propylene linker by arylpiperazine pharmacophore with fluorine substituents and by benzoyl moiety.

Discovery of First-in-Class Peptidomimetic Neurolysin Activators Possessing Enhanced Brain Penetration and Stability.

Peptidase neurolysin (Nln) is an enzyme that functions to cleave various neuropeptides. Upregulation of Nln after stroke has identified the enzyme as a critical endogenous cerebroprotective mechanism and validated target for the treatment of ischemic stroke. Overexpression of Nln in a mouse model of stroke results in dramatic improvement of stroke outcomes, while pharmacological inhibition aggravates them. Activation of Nln has therefore emerged as an intriguing target for drug discovery efforts for ischemic stroke. Herein, we report the discovery and hit-to-lead optimization of first-in-class Nln activators based on histidine-containing dipeptide hits identified from a virtual screen. Adopting a peptidomimetic approach provided lead compounds that retain the pharmacophoric histidine moiety and possess single-digit micromolar potency over 40-fold greater than the hit scaffolds. These compounds exhibit 5-fold increased brain penetration, significant selectivity over highly homologous peptidases, greater than 65-fold increase in mouse brain stability, and 'drug-like' fraction unbound in the brain.

Synthesis, characterization, biological evaluation, and molecular docking approach of nickel (II) complexes containing O, N‐donor chelation pattern of sulfonamide‐based Schiff bases

AbstractA series of Schiff bases (L1–L4) that possess in their structure bioactive sulfonamide group and their nickel (II) complexes have been synthesized. Microanalytical analyses, various spectroscopic methods such as Fourier transform infrared spectroscopy (FT‐IR), 1H nuclear magnetic resonance (NMR), 13C NMR, UV–Vis, and MS, are used to explore the nature of bonding and to elucidate the chemical structures. The analytical and magnetic values suggest a range of stoichiometries 1:1, 1:2, and 2:1 (M:L) for the synthesized complexes of almost square planar geometry. The spectral comparative interpretation reveals that L1 and L2 coordinate to the central Ni (II) in tetradentate ONON donor sequence, whereas L3 and L4 in bidentate ON pattern through deprotonated phenolic‐O and the azomethine‐N. Density functional theory (DFT) and MOE‐docking approaches are used to evaluate the molecular parameters and the binding propensity of the synthesized ligands and their complexes with 3s7s protein and to signify their inhibition strength. Besides, the anticancer, antimicrobial and antifungal activities have been screened against number of tumor cells and human pathogen strains. These in vitro studies reveal that Schiff base L4 and its complex, [Ni(L4‐H)(OAc)(H2O)], have superior activities reflecting the importance of inserting bioactive pendant substituents such as thiazole ring and 3‐fluorophenylazo to the pharmacophoric sulfonamide moiety. Moreover, some of the synthesized Ni (II) complexes display promising therapeutic effects as novel non‐platinum antitumor agents after further preclinical investigations.

Design and synthesis of novel quinazolinone-pyrazole derivatives as potential α-glucosidase inhibitors: Structure-activity relationship, molecular modeling and kinetic study

In this study, a new series of quinazolinone-pyrazole hybrids were designed, synthesized and screened for their α-glucosidase inhibitory activity. The results of the in vitro screening indicated that all the molecular hybrids exhibited more inhibitory activity (IC50 values ranging from 60.5 ± 0.3 µM-186.6 ± 20 μM) in comparison to standard acarbose (IC50 = 750.0 ± 10.0 µM). Limited structure–activity relationship suggested that the variation in the inhibitory activities of the compounds affected by different substitutions on phenyl rings of diphenyl pyrazole moiety. The enzyme kinetic studies of the most potent compound 9i revealed that it inhibited α-glucosidase in a competitive mode with a Ki of 56 μM. Molecular docking study was performed to predict the putative binding interaction. As expected, all pharmacophoric moieties used in the initial structure design playing a pivotal role in the interaction with the binding site of the enzyme. In addition, by performing molecular dynamic investigation and MM-GBSA calculation, we investigated the difference in structural perturbation and dynamic behavior that is observed over α-glycosidase in complex with the most active compound and acarbose relative to unbound α-glycosidase enzyme.

Design, Synthesis and Molecular Docking of New Benzimidazole Derivatives of Potential Antimicrobial Activity as DNA Gyrase and Topoisomerase IV Inhibitors

A new series of benzimidazole derivatives 3a-3d, 4a-4c, 8a-8d, 9a,9b, 10a-10d and 11 was synthesized and evaluated as antimicrobial agents against various gram-positive, gram-negative bacteria and fungi using vibramycin and fluconazole as positive controls for the antibacterial and antifungal activities, respectively. The examined microbial strains showed variable sensitivities against the target compounds.The examined microbial strains showed variable sensitivities against the target compounds. The minimum inhibitory concentration (MIC) was determined for the compounds showed zone of inhibition ≥ 16 mm (4a, 4c, 8a, 10a). The latter derivatives were also examined as S. aureus DNA gyrase/topoisomerase IV inhibitors. The compounds 4a, and 8a represented the most promising activity for both enzymes in ATPase assay (IC50 4a 0.39, 0.52 and 8a 0.66, 0.28 µM respectively) as well as the safest profile against the human normal WI38 cells upon comparing with Ciprofloxacin and Novobiocin. Compounds 8a showed dual inhibitory effect against both targets DNA gyrase and topoisomerase IV in supercoiling and decatenation assay (IC50 0.443 and 1.15 µM respectively). Both compounds 4a and 8a can be considered as lead compounds for further structural modifications to obtain more potent DNA gyrase and topoisomerase inhibitors as antibacterial agents. Molecular docking study was performed for the most promising compounds to explore the pharmacophoric moieties that governed their binding with amino acid residues of DNA gyrase and topoisomerase IV using MOE software. The results revealed a binding mode and docking scores comparable to those of a reference ligand and consistent with their DNA gyrase and topoisomerase IV inhibition activity.

Multifunctional Isosteric Pyridine Analogs-Based 2-Aminothiazole: Design, Synthesis, and Potential Phosphodiesterase-5 Inhibitory Activity.

The elaboration of new small molecules that target phosphodiesterase enzymes (PDEs), especially those of type 5 (PDE5), is an interesting and emerging topic nowadays. A new series of heterocycle-based aminothiazoles were designed and synthesized from the key intermediate, 3-oxo-N-(thiazol-2-yl)butanamide (a PDE5 inhibitor that retains its amidic function), as an essential pharmacophoric moiety. The PDE5 inhibitors prevent the degradation of cyclic guanosine monophosphate, thereby causing severe hypotension as a marked side effect. Hence, an in vivo testing of the target compounds was conducted to verify its relation with arterial blood pressure. Utilizing sildenafil as the reference drug, Compounds 5, 10a, and 11b achieved 100% inhibitions of PDE5 without significantly lowering the mean arterial blood pressures (115.95 ± 2.91, 110.3 ± 2.84, and 78.3 ± 2.57, respectively). The molecular docking study revealed that the tested compounds exhibited docking poses that were similar to that of sildenafil (exploiting the amide functionality that interacted with GLN:817:A). The molecular shape and electrostatic similarity revealed a comparable physically achievable electrostatic potential with the reference drug, sildenafil. Therefore, these concomitant results revealed that the tested compounds exerted sildenafil-like inhibitory effects (although without its known drawbacks) on blood circulation, thus suggesting that the tested compounds might represent a cornerstone of beneficial drug candidates for the safe treatment for erectile dysfunction.

Anti-Inflammatory and Analgesic Activities of 7-Chloro-4-(Piperazin-1-yl) Quinoline Derivative Mediated by Suppression of InflammatoryMediators Expression in Both RAW 264.7 and Mouse Models

Background: 4-Aminoquinoline derivatives possess various potential biological properties.The introduction of additional piperazine heterocyclic pharmacophoric moiety tends to haveprofound impact in increasing the activity. The present work was undertaken to investigate thein-vitro and in-vivo anti-inflammatory activity as well as the peripheral and central analgesicactivities of compound 1-(4-(7-chloroquinoline-4-yl)piperazin-1-yl)-2-(4-phenylpiperazin-1-yl)ethanone (5) in experimental models. Methods: The percentage inhibition of the lipopolysaccharide induced NO release of 7-chloro-4-(piperazin-1-yl)quinoline derivatives 1-9 was determined in RAW 264.7 murine macrophagemodel. Western blot analysis was performed to evaluate the effect of compound 5 on proteinexpression of inducible nitric oxide synthase (iNOS). Gene expression of inflammatory markerswas evaluated using real-time polymerase chain reaction. The peripheral and central analgesicactivities of compound 5 were evaluated in mice using writhing and hot-plate tests, respectively.Anti-inflammatory activity was assessed using carrageenan-induced paw edema assay in miceand serum NO and COX-2 levels were measured. Results: Compound 5 demonstrated the highest NO inhibitory activity that was accompaniedby inhibition of iNOS protein expression and decreased gene expression levels of inflammatorymarkers. It revealed a potential peripheral analgesic effect through inhibition of abdominalwrithing in mice treated with doses of 15 and 30 mg/kg and its effect was comparable to diclofenacsodium. Compound 5 possessed an analgesic activity starting from 15 min post administrationand reached its peak at 45 min which was significantly higher than that of tramadol hydrochloridesuggesting its potential as central analgesic agent. It also showed percentage of inhibition ofedema of 34, 50 and 64% at 1, 2, and 3 h respectively, post carrageenan challenge together with asignificant decrease in serum NO and COX-2 levels. Conclusion: The remarkable anti-inflammatory and analgesic activities of compound 5 couldbe attributed to the advantageous introduction of the heterocyclic 7-chloro-4-(piperazin1-yl)quinoline scaffold incorporated with N-phenylpiperzine functional groups linked together withthe ethanone pharmacophoric chain.

The Binding of Remdesivir to SARS-CoV-2 RNA-Dependent RNA Polymerase May Pave The Way Towards the Design of Potential Drugs for COVID-19 Treatment.

We seek to provide an understanding of the binding mechanism of Remdesivir, as well as structural and conformational implications on SARS-CoV-2 virus RNA-dependent RNA polymerase upon its binding and identify its crucial pharmacophoric moieties. The coronavirus disease of 2019 (COVID-19) pandemic had infected over a million people, with 65,000 deaths as of the first quarter of 2020. The current limitation of effective treatment options with no approved vaccine or targeted therapeutics for the treatment of COVID-19 has posed serious global health threats. This has necessitated several drug and vaccine development efforts across the globe. To date, the farthest in the drug development pipeline is Remdesivir. We performed the molecular dynamics simulation, quantified the energy contributions of binding site residues using per-residue energy decomposition calculations, and subsequently generated a pharmacophore model for the identification of potential SARS-CoV-2 virus RNA-dependent RNA polymerase inhibitors. Integrative molecular dynamics simulations and thermodynamic calculations coupled with advanced post-molecular dynamics analysis techniques were employed. Our analysis showed that the modulatory activity of Remdesivir is characterized by an extensive array of high-affinity and consistent molecular interactions with specific active site residues that anchor Remdemsivir within the binding pocket for efficient binding. These residues are ASP452, THR456, ARG555, THR556, VAL557, ARG624, THR680, SER681, and SER682. Results also showed that Remdesivir binding induces minimal individual amino acid perturbations, subtly interferes with deviations of C-α atoms, and restricts the systematic transition of SARS-CoV-2 RNA-dependent RNA polymerase from the "buried" hydrophobic region to the "surface-exposed" hydrophilic region. We also mapped a pharmacophore model based on the observed high-affinity interactions with SARSCoV- 2 virus RNA-dependent RNA polymerase, which showcased the crucial functional moieties of Remdesivir and was subsequently employed for virtual screening. The structural insights and the provided optimized pharmacophoric model would augment the design of improved analogs of Remdesivir that could expand treatment options for COVID-19.

Novel 2-(5-Aryl)thiophen-2-yl)benzimidazoles; Design, Synthesis and In vitro Evaluation Against Cercarial Phase of Schistosoma mansoni

Background: Literature survey has pointed out that Benzimidazoles represent an interesting class of anthelmintics, of which several potent members were developed. Objective: Benzimidazoles hybridized with pharmacophoric moieties possessing anthelmintic activity were designed, synthesized to be evaluated against cercaria. Methods: Structural modification was achieved through 2- and 5-positions. Moreover, an in vitro cercarial assay was adopted to evaluate target compounds. Results and Discussion: Biological screening revealed that compound 3h showed significant activity with a survival index of 35% at a 100 μg/mL concentration. Whereas, compounds 3a and 3c showed moderate activity, the rest of the tested compounds exhibited low activity. Conclusion: The current study evidenced that the new hybrids "benzimidazole-thiophen-aryl" are successful as cercacidal agents. Further studies of this novel tri-ring system are suggested on adult worms of S. mansoni.

Natural Sesquiterpene Lactones in the Prevention and Treatment of Inflammatory Disorders and cancer: A Systematic Study of this Emerging Therapeutic Approach based on Chemical and Pharmacological Aspect

Background and Introduction: Sesquiterpene lactones are a class of secondary metabolite that contains sesquiterpenoids and lactone ring as pharmacophore moiety. A large group of bioactive secondary metabolites such as phytopharmaceuticals belong to this category. From the Asteraceae family-based medicinal plants, more than 5,000 sesquiterpene lactones have been reported so far. Sesquiterpene lactone-based pharmacophore moieties hold promise for broad-spectrum biological activities against cancer, inflammation, parasitic, bacterial, fungal, viral infection and other functional disorders. Moreover, these moiety based phytocompounds have been highlighted with a new dimension in the natural drug discovery program worldwide after the 2015 Medicine Nobel Prize achieved by the Artemisinin researchers. Objective: These bitter substances often contain an α, β-unsaturated-γ-lactone as a major structural backbone, which in recent studies has been explored to be associated with anti-tumor, cytotoxic, and anti-inflammatory action. Recently, the use of sesquiterpene lactones as phytomedicine has been increased. This study will review the prospect of sesquiterpene lactones against inflammation and cancer. Methods: Hence, we emphasized on the different features of this moiety by incorporating its structural diversity on biological activities to explore structure-activity relationships (SAR) against inflammation and cancer. Results: How the dual mode of action such as anti-inflammatory and anti-cancer has been exhibitedby these phytopharmaceuticals will be forecasted in this study. Furthermore, the correlation of anti-inflammatory and anti-cancer activity executed by the sesquiterpene lactones for fruitful phytotherapy will also be revealed in the present review in the milieu of pharmacophore activity relation and pharmacodynamics study as well. Conclusion: So, these metabolites are paramount in phytopharmacological aspects. The present discussion on the future prospect of this moiety based on the reported literature could be a guide for anti-inflammatory and anti-cancer drug discovery programs for the upcoming researchers.

A Review on Antimalarial 1,2,4-Trioxane Derivatives

Malaria in recent years becomes a major health hitch globally due to the surfacing of multidrug-resistant strains of Plasmodium falciparum parasite. In recent times, artemisinin (ART)-based drugs and combination therapies become the drugs of preference for the treatment and prophylaxis of resistant P. falciparum malaria. Endoperoxide compounds natural, semi-synthetic or synthetic signifying a massive number of antimalarial agents which possess a wide structural miscellany with needed antimalarial effectiveness against resistant P. falciparum malaria. The 1,2,4-trioxane ring system deficient the lactone ring which constitutes the most significant endoperoxide structural scaffold which is believed to be the key pharmacophoric moiety and is principally responsible for the pharmacodynamic potential of endoperoxide-based antimalarials. This becomes the main reason for the research related to endoperoxide particularly 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-tetraoxane-based scaffolds gaining the noteworthy interest in recent years for developing antimalarial drugs against resistant malaria. In this paper, a comprehensive endeavour has been made to review the development of different endoperoxide antimalarial agents and structural diversity of endoperoxide molecules derived from 1,2,4-trioxane- based structural scaffolds.
 Keywords: Endoperoxide; 1,2,4-trioxane; pharmacophores; artemisinin; antimalarial.

Usnic Acid Conjugates with Monoterpenoids as Potent Tyrosyl-DNA Phosphodiesterase 1 Inhibitors.

Hybrid molecules created from different pharmacophores of natural and synthetic equivalents are successfully used in pharmaceutical practice. One promising target for anticancer therapy is tyrosyl-DNA phosphodiesterase 1 (Tdp1) because it can repair DNA lesions caused by DNA-topoisomerase 1 (Top1) inhibitors, resulting in drug resistance. In this study, new hybrid compounds were synthesized by combining the pharmacophoric moiety of a set of natural compounds with inhibitory properties against Tdp1, particularly, phenolic usnic acid and a set of different monoterpenoid fragments. These fragments were connected through a hydrazinothiazole linker. The inhibitory properties of the new compounds mainly depended on the structure of the terpenoid moieties. The two most potent compounds, 9a and 9b, were synthesized from citral and citronellal, which contain acyclic fragments with IC50 values in the range of 10-16 nM. Some synthesized derivatives showed low cytotoxicity against HeLa cells and increased the effect of the Top1 inhibitor topotecan in vitro by three to seven times. These derivatives may be considered as potential agents for the development of anticancer therapies when combined with Top1 inhibitors.

Hybrid molecules based on 1,3,5-triazine as potential therapeutics: A focused review.

Majority of the representative drugs customarily interact with multiple targets manifesting unintended side effects. In addition, drug resistance and over expression of the cellular efflux-pumps render certain classes of drugs ineffective. With only a few innovative formulations in development, it is necessary to identify pharmacophores and novel strategies for creating new drugs. The conjugation of dissimilar pharmacophoric moieties to design hybrid molecules with an attractive therapeutic profile is an emerging paradigm in the contemporary drug development regime. The recent decade witnessed the remarkable biological potential of 1,3,5-triazine framework in the development of various chemotherapeutics. The appending of the 1,3,5-triazine nucleus to biologically relevant moieties has delivered exciting results. The present review focuses on 1,3,5-triazine based hybrid molecules in the development of pharmaceuticals.