Analogue 1b Research Articles

Design, synthesis, and anticancer evaluation of novel N-[5-(1,3,4,5-tetrahydroxycyclohexyl)-1,3,4-thiadiazole-2-yl] benzamide analogues through integrated computational and experimental approaches

BackgroundThe main aim of the current study is to develop, synthesize, in silico, in vitro and in vivo potentials of N-[5-(1,3,4,5-tetrahydroxycyclohexyl)-1,3,4-thiadiazole-2-yl] benzamide derivatives for a possible anticancer drug to improve their efficiency and selectivity against cancer cells, computational approaches aided in the rational design of these chemicals. Spectroscopic methods verified the chemical structures of the target compounds. The structures of the synthesized analogs were determined by elemental analysis, IR, 1H NMR, 13C NMR and MS. Structure shows the presence of 1,3,4, thiadiazole also responsible for anticancer activity. The 10 analogs were synthesized and showed encouraging anticancer efficacy in preliminary biological evaluation, suggesting they might be suitable lead candidates for more optimization and preclinical exploration.ResultN-[5-(1,3,4,5-tetrahydroxycyclohexyl)-1,3,4-thiadiazole-2-yl] benzamide derivatives were synthesized (5a-5j) showed an optimum IC50 value in in vitro activity by SRB assay using MCF-7 as a strain, and the few selected analogs 5b,5 g & 5 h were subjected for in vivo anticancer activity by DMBA induction of tumors in mice.ConclusionThrough a computational and experimental approach, this study results a way for newer derivatives for the class of anticancer drugs.

Transition metal complexes of benzimidazole-based ligands: Synthesis, characterization, biological, and catecholase activities

Heterocyclic ligands 5a and 5b and their metal complexes (1–10) and (11–20) respectively, were synthesized and characterized by mass spectrometry, FT-IR, ESR, 1H, 13C NMR and UV–visible spectroscopy. In vitro antifungal activity of the heterocyclic analogs 5a, 5b and metal complexes (1–20) was evaluated against the fungal strains: Candida albicans, Candida glabrata, and Candida tropicalis., The results showed that Fe(III) 2 and Co(II) complex 13 display considerable antifungal activity with MIC values of 350, 375 and 435 μg/mL and 450, 455, and 455 μg/mL against C. albicans, C. glabrata, and C. tropicalis, respectively. Promising 5a, 5b, Fe(III) 2, and Co(II) complex 13 show groove binding mode with Ct-DNA, which has been confirmed by several techniques, including UV–visible, fluorescence spectroscopy, and cyclic voltammetry. PDB ID: 1BNA was used for the molecular docking investigation of the heterocyclic analogs 5a and 5b. The active Fe(III) complex 2 and Co(II) complex 13 are effectively catalyzed for the oxidation of catechol in acetonitrile to its corresponding quinone with turnover number 5.44 × 104 and 9.78 × 104 h−1, respectively with first order that follow Michaelis-Menten enzymatic kinetics. The pharmacokinetics properties of the all compounds showed good oral bioavailability. Antioxidant potential of ligands 5a, 5b, Fe(III) 2 and Co(II) complex 13 was further approximated through DPPH free radical and H2O2 with remarkable antioxidant activity.

Facile one-pot synthesis of N-pyridinylaminonaphthol derivatives and their antibacterial evaluation against multidrug-resistant Staphylococcus aureus.

The escalating severity of the menace posed by bacterial resistance has rendered the existing antibiotics less effective, thus necessitating the discovery of new antibacterial agents. The current study reports the exploration of substituted N-pyridinylaminonaphthols produced by a straightforward, one-pot multicomponent reaction process as antibacterial agents. The synthesized derivatives were assessed in vitro for their antibacterial properties against a panel of bacterial pathogens. The analogs 4b, 4g, 4h, 4i, 4j, 4l, 4r, and 4t exhibited potent inhibitory activity with minimum inhibitory concentration (MIC) values of 1-2 µg/mL. Notably, 4b, 4l, and 4t displayed an excellent selectivity index. Additionally, they were active against the multidrug-resistant bacterial strains, with 4l exhibiting the best activity against methicillin-resistant Staphylococcus aureus and vancomycin resistant staphylococcus aureus with a MIC of 1 µg/mL. 4l showed synergism with gentamycin and showed bactericidal property in a concentration-dependent manner. Furthermore, the molecule 4l inhibited the DNA gyrase supercoiling activity. Absorption, distribution, metabolism, excretion/toxicity parameters and pharmacokinetic properties were assessed via in silico techniques, which elucidate the potential mode of action. These findings demonstrate the potential of the N-pyridinylaminonaphthol derivatives as antibacterial agents against multidrug-resistant S. aureus.

A click-chemistry based strategy for synthesizing coumarin piperazine analogues: Assessment of anti-tubercular, anti-cancer, anti-inflammatory and antioxidant potentials

In this study, a novel series of coumarin piperazine analogues were synthesized using Click chemistry approach. Thus synthesized compounds (8a-j) were evaluated for their pharmacological potentialities. These compounds subjected for evaluation of their anti-tubercular, anti-cancer, anti-inflammatory, and antioxidant properties. Results revealed that analogues 8b, 8d, 8i and 8h are found to be the promising drug-like candidates against Mycobacterium tuberculosis H37Rv strain exhibiting more potent activity than isoniazid with MIC of 2.24, 1.04, 3.72, 5.35 µM respectively. Furthermore, the compound 8d displayed better anti-inflammatory and antioxidant activity with IC50 values of 66.43 µM and 69.14 µM respectively. Molecular docking studies insights into the binding affinities and interactions with a target protein. The in silico ADME profiles supported their pharmacokinetic viability. Predominantly, compound 8d exhibited anticancer activity with IC50 values of 12.42 µM and 26.16 µM with reference to HeLa and MCF-7respectively by inhibiting acetyl-CoA synthetase. These findings highlight more specifically the compound 8d as a potent anti-cancer agent.

Destruxin E backbone modification effects on osteoclast Morphology: Synthesis and SAR study of N-Desmethyl and N-Methyl analogs

The design and synthesis of N-desmethyl and N-methyl destruxin E analogs have been demonstrated. The X-ray single crystal structure of destruxin E (1a) revealed a stable three-dimensional (3D) structure, including a s-cis amide bond at the MeVal–MeAla moiety and two intramolecular hydrogen bonds between NH(β-Ala) and OC(Ile) and between NH(Ile) and OC(β-Ala). N-Desmethyl analogs 2a (MeAla → Ala) and 2b (MeVal → Val) were synthesized through macrolactonization similar to our previously reported synthesis of 1a. Conversely, for the synthesis of N-methyl analogs 2c (Ile → MeIle) and 2d (β-Ala → Meβ-Ala), macrolactonization did not proceed; therefore, cyclization precursors 10c and 10d were designed to maintain the intramolecular hydrogen bonds described above during their cyclization. The macrolactamization proceeded despite the presence of a less reactive N-methylamino group at the N-terminus in both cases. Analog 2a, which exhibits multiple conformers in solutions, was inactive at 50 μM, whereas analog 2b, which exhibits a conformation similar to that of 1a in solutions, exhibited morphological changes against osteoclast-like multinuclear cells at 1.6 μM. The activity of the MeIle analog 2c, which cannot take the intramolecular hydrogen bond (Ile)NH•••OC(β-Ala) in 1a, was markedly diminished compared with that of 1a, and that of the Meβ-Ala analog 2d, which cannot take the intramolecular hydrogen bond (β-Ala)NH•••OC(Ile) in 1a, was further reduced to one-fourth of that of 2c. The overall results indicate that both the s-cis amide bond at the MeVal–MeAla moiety and two intramolecular hydrogen bonds (β-Ala)NH•••OC(Ile) and (Ile)NH•••OC(β-Ala) are important for constraining the conformation of the macrocyclic peptide backbone in destruxin E, thereby exhibiting its potent biological activity.

Designing Antitrypanosomal and Antileishmanial BODIPY Derivatives: A Computational and In Vitro Assessment.

Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current antiprotozoal treatments and the lack of approved vaccines. Considering the demand for novel therapeutic drugs, a series of BODIPY derivatives with several functionalizations at the meso, 2 and/or 6 positions of the core were synthesized and characterized. The in vitro activity against Trypanosoma brucei and Leishmania major parasites was carried out alongside a human healthy cell line (MRC-5) to establish selectivity indices (SIs). Notably, the meso-substituted BODIPY, with 1-dimethylaminonaphthalene (1b) and anthracene moiety (1c), were the most active against L. major, displaying IC50 = 4.84 and 5.41 μM, with a 16 and 18-fold selectivity over MRC-5 cells, respectively. In contrast, the mono-formylated analogues 2b and 2c exhibited the highest toxicity (IC50 = 2.84 and 6.17 μM, respectively) and selectivity (SI = 24 and 11, respectively) against T. brucei. Further insights on the activity of these compounds were gathered from molecular docking studies. The results suggest that these BODIPYs act as competitive inhibitors targeting the NADPH/NADP+ linkage site of the pteridine reductase (PR) enzyme. Additionally, these findings unveil a range of quasi-degenerate binding complexes formed between the PRs and the investigated BODIPY derivatives. These results suggest a potential correlation between the anti-parasitic activity and the presence of multiple configurations that block the same site of the enzyme.

Guanidine-to-piperidine switch affords high affinity small molecule NPFF ligands with preference for NPFF1-R and NPFF2-R subtypes

The Neuropeptide FF (NPFF) receptor system is known to modulate opioid actions and has been shown to mediate opioid-induced hyperalgesia and tolerance. The lack of subtype selective small molecule compounds has hampered further exploration of the pharmacology of this receptor system. The vast majority of available NPFF ligands possess a highly basic guanidine group, including our lead small molecule, MES304. Despite providing strong receptor binding, the guanidine group presents a potential pharmacokinetic liability for in vivo pharmacological tool development. Through structure-activity relationship exploration, we were able to modify our lead molecule MES304 to arrive at guanidine-free NPFF ligands. The novel piperidine analogues 8b and 16a are among the few non-guanidine based NPFF ligands known in literature. Both compounds displayed nanomolar NPFF-R binding affinity approaching that of the parent molecule. Moreover, while MES304 was non-subtype selective, these two analogues presented new starting points for subtype selective scaffolds, whereby 8b displayed a 15-fold preference for NPFF1-R, and 16a demonstrated an 8-fold preference for NPFF2-R. Both analogues showed no agonist activity on either receptor subtype in the in vitro functional activity assay, while 8b displayed antagonistic properties at NPFF1-R. The calculated physicochemical properties of 8b and 16a were also shown to be more favorable for in vivo tool design. These results indicate the possibility of developing potent, subtype selective NPFF ligands devoid of a guanidine functionality.

Discovery of Dehydroabietylamine Derivatives as Antibacterial and Antifungal Agents.

A diverse array of biologically active derivatives was derived by modifying the chemically active sites of dehydroabietylamine. Herein, we describe the synthesis of a new series of C-19-arylated dehydroabietylamine derivatives using a palladium-catalyzed C(sp3)-H activation reaction. Five analogues (3b, 3d, 3h, 3n, and 4a) exhibited antibacterial activity against Escherichia coli. Compound 4a exhibited strong inhibitory activity against DNA Topo II and Topo IV. Molecular docking modeling indicated that it can bind effectively to the target through interactions with amino acid residues. The synthesized compounds were tested in vitro for their antifungal activity against six common phytopathogenic fungi. The mechanism of action of compound 4c against Rhizoctorzia solani was investigated, revealing that it disrupts the morphology of the mycelium and enhances cell membrane permeability.

Morphing cholinesterase inhibitor amiridine into multipotent drugs for the treatment of Alzheimer's disease

The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties to generate novel MTDLs endowed with additional properties like N-methyl-d-aspartate (NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridine-based drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy.

Guided isolation of enantiomeric lignans from Cimicifuga heracleifolia Kom. by antioxidant activity and molecular networking

Under the guidance of antioxidant evaluation combined with molecular networking, six pairs of enantiomeric lignans including seven undescribed ones (1a, 2a/2b−4a/4b), along with five known analogs (1b, 5a/5b−6a/6b) were isolated from Cimicifuga heracleifolia Kom. Their structures were determined by extensive spectroscopic data analysis, including HRESIMS, 1D and 2D NMR, experimental and calculated ECD. All the enantiomeric isolates were evaluated for antioxidation by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 2′-azino-bis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) free radical scavenging tests. Compounds 1a and 3a/3b exhibited great DPPH and ABTS scavenging activities. The results are of great value for understanding structurally interesting enantiomeric lignans with antioxidant activity from C. heracleifolia in depth and providing its further development in functional evaluation and drug development.

Synthesis, computational study, and antileishmanial and antifungal evaluation of phenoxyacetophenone hydrazones bearing a 4-arylthiazole moiety

A series of new phenoxyacetophenone hydrazones 6a-l bearing a 4-arylthiazole moiety were synthesized and tested as antileishmanial agents. After spectroscopic and computational characterization of the synthesized compounds, their antileishmanial and antifungal activities were investigated in vitro. All compounds exhibited good antileishmanial activity, demonstrating IC50 values = 3.63–17.4 μg/ml against promastigotes of Leishmania major. Certainly, the para-tolyl analog 6b showed the most potent activity against promastigotes. Compounds 6b, 6c, 6f, and 6i-6k with good activity against promastigotes (IC50 values ≤ 7.59 μg/ml) were subjected to further bioassay on the amastigotes of L. major, as well as cytotoxicity evaluation against host-cell macrophages. The representative compounds displayed substantial anti-amastigote activity (IC50 values ≤ 21.3 μg/ml) with good selectivity index (SI > 18). Additionally, the in vitro antifungal screening against yeasts, molds and dermatophytic fungi revealed that several compounds had respectable activity against dermatophytes. These results demonstrate that the thiazolyl-hydrazones 6 are proper leads for further design and development of potential antileishmanial agents.

Synthesis, Bioactivity Evaluation, and Molecular Docking Study of Tranilast Analogs as Anticancer Agents

Abstract: Developing new agents with higher therapeutic potential and less toxicity to overcome the limitations of chemotherapy in cancer treatment has been identified as an urgent need and priority. Recent studies have shown promising anticancer activities of tranilast when used alone or in combination with other chemotherapeutic agents. This research aims to synthesize tranilast analogs, evaluate in vitro anticancer activity, and dock into the TGFβ1 target to find stronger anticancer agents. Tranilast (5a) and analogs (5b–f) were synthesized from anthranilic acid derivatives, Meldrum’s acid, and benzaldehydes based on the Knoevenagel-Doebner reaction. The compounds were evaluated for in vitro cytotoxicity activity by MTT assay and docked into the TGFβ1 target using AutoDockTools–1.5.6. Tranilast (5a) and seven analogs (5b–h) were successfully synthesized and analyzed for their structures. Four analogs (5b–d, 5f) possessed stronger effects on both HepG2 and MCF-7 cell lines with proliferation inhibitions at concentrations of 100 μg/mL in the range of 41 to 95% compared to tranilast (16.95% and 22.64%). Compound 5f exhibited the most potent analog with IC50 = 27.57 μg/mL (HepG2) and 16.67 μg/mL (MCF-7) compared to tranilast (IC50 > 100 μg/mL) and had good binding affinity on TGFβ1 target (docking score ˗7.35 Kcal/mol). Four of seven tranilast analogs possessed stronger cytotoxicity activity on both HepG2 and MCF-7 cell lines compared to that of the parent compound, tranilast. Notably, compound 5f displayed the most potent activity and good binding affinity on the TGFβ1 target, indicating the potential for further study as an anticancer agent.

Development of 1,3a,6a-triazapentalene derivatives as practical erasable fluorescent cell staining reagents

1,3a,6a-Triazapentalene (TAP) derivatives were developed as erasable fluorescent cell staining reagents that can be used with a confocal laser microscope. To enhance the utility of previously developed erasable fluorescent cell staining reagents such as 2-biphenyl-TAP (1a) for practical applications in confocal laser microscopy, a carbonyl group with strong electron-withdrawing properties was introduced between the TAP core skeleton and the biphenyl group, leading to a longer wavelength shift in absorption and emission maxima. While the analog 1b, featuring only the carbonyl group insertion, declined significantly in fluorescence intensity, the two-carbon extended ketone analog 1d showed a desirable shift in absorption maximum towards longer wavelengths, green fluorescence, and high fluorescence intensity. Cell staining experiments using 1d demonstrated its usefulness, including rapid staining, erasable fluorescent staining, and compatibility with confocal laser microscopy employing a standard filter.

Design, synthesis, and molecular docking study of N-(arylsulfonyl)-l-proline-piperazine hybrids tethered with pyrazole/benzofuran moiety as antimicrobial agents

In search of novel antimicrobial agents, new series of N-(arylsulfonyl)-l-proline-derived hybrids tethered with pharmacologically attractive cores as 1-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazine and 5-(Piperazin-1-yl)benzofuran-2-carboxamide were synthesized and evaluated for in vitro antimicrobial potential against six different representative human pathogenic strains. Among all, N-acetyl derivative 5e containing phenylpyrazolyl moiety displayed an appreciable inhibitory value (MIC: 107 µg/mL) with noteworthy binding energy (–6.65 kcal/mol) against S. aureus as compared to standard ampicillin (MIC: 250 µg/mL). The N-phenyl-pyrazolyl containing analogue 5b elicited comparable activity against E. coli and P. aeruginosa with MIC values of 104 µg/mL and 121 µg/mL, respectively. Moreover, 5b, 5d, and 6c showed appreciable antioxidant activity (IC50:19.25–20.69 µg/mL) as compared to butylated hydroxytoluene (BHT, IC50:16.47 μg/mL). Molecular docking studies against target tyrosyl-tRNA synthetase (TyrRS) of S. aureus (PDB: 1JIJ) revealed the potential binding mode of the ligands to the appropriate site of targets and their plausible mechanism of in vitro antibacterial activity.

Synthesis and pharmacological characterization of conformationally restricted 2-amino-Adipic acid analogs and carboxycyclopropyl glycines as selective metabotropic glutamate 2 receptor agonists

The metabotropic glutamate (Glu) receptors (mGluRs) are G-protein coupled receptors, which play a central role in modulating excitatory neurotransmission in the central nervous system (CNS). Thus, the development of tool compounds thereto, continues to interest the scientific community. In this study, we report the design and synthesis of new conformationally restricted 2-aminoadipic acid (2AA) 2–4, and glutamic acid 5, 6 analogs, which share the cyclopropane ring as the restrictor. The analogs were characterized at rat mGlu1−8 in an IP-One functional assay. While the 2AA analogs 3a, 4a and CCG-I analog 5a were shown to be selective mGlu2 agonists with low micromolar potencies, CCG-II analog 5b was shown to be a potent full agonist at mGlu2 (EC50 = 82 nM) with ∼15-fold selectivity over mGlu3, >25-fold selectivity over group III, and >60-fold selectivity over group I subtypes. An in silico study was performed to address this significant change (>3500 fold) in potency upon introduction of this methyl group (L-CCG-II vs 5b).

Structure-constraint induced increase in Lewis acidity of tris(ortho-carboranyl)borane and selective complexation with Bestmann ylides.

The Lewis acidity of tris(ortho-carboranyl)borane has been slightly increased by mimicking the structural evolution from triarylborane to 9-aryl-9-borafluorene. The o-carborane-based analogue (C2B10H10)2B(C2B10H11), obtained via salt elimination between LiC2B10H11 and (C2B10H10)2BBr, has been fully characterized. Gutmann-Beckett and computational fluoride/hydride ion affinity (FIA/HIA) studies have confirmed the increase in Lewis acidity, which is attributable to structural constraint imposed by the CC-coupling between two carboranyl groups. Selective complexation of (C2B10H10)2B(C2B10H11) with Bestmann ylides R3PCCO (R = Ph, Cy) has been achieved, enabling further conversion into the zwitterionic phospholium salt through NHC-catalyzed proton transfer.

Novel Amide Derivatives of Pyrimidinediones: Design, Synthesis, Characterization, Biological Assessment, ADMET and in silico Docking Studies

In an attempt to synthesize new chemical entities with promising biological activity, a set of six novel pyrimidinedione analogues 6(a-f) was prepared. The compound 4 was coupled with different amines by using HBTU as a coupling reagent. The derivatives were characterized by 1HNMR,13CNMR and HRMS. The analogues were evaluated for their antibacterial and antioxidant activity. The DPPH and ABTS methods were used to test the antioxidant activity of the moieties. Among the six pyrimidinedione analogues, 6b, 6d, and 6f exhibited significant antioxidant effects. The paper disc diffusion method was adopted to evaluate the antibacterial activity of the samples. The analogues 6b, 6c and 6e exhibited potency against gram-negative and gram-positive pathogens. Further, to evaluate the binding abilities of the analogues to the protein active sites, molecular docking studies were performed. The results of the docking studies were found to be consistent with the antibacterial potential of the analogues. The efficacy of these analogues provides insight into their use as novel antioxidant and antibacterial agents.

Structure-based design, and development of amidinyl, amidoximyl and hydroxamic acid based organic molecules as novel antimalarial drug candidates

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 Plasmodium falciparum 6-pyruvoyltetrahydropterin synthase (PfPTPS), 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 (1c, 1d, 2b, and 3b), with a focus on their ability to bind to the Zn2+ present in the active site of PfPTPS. The syntheses of these compounds were accomplished through various multi-step synthetic pathways and their structural identities were confirmed using 1H and 13C NMR spectra, mass spectra, and elemental analysis. The compounds were screened for their antiplasmodial activity against the NF54 strain of P. falciparum and in vitro cytotoxicity testing was performed using L-6 cells. The in vivo acute toxicity of the compounds was evaluated in mice. Docking studies of the compounds with the 3D structure of PfPTPS revealed their strong binding affinities, with compound 3b exhibiting notable metal–acceptor interaction with the Zn2+ in the protein binding pocket thereby positioning it as a lead compound for PfPTPS inhibition. The in vitro antiplasmodial studies revealed moderate efficacies against the Pf NF54 strain, particularly compounds 1d and 3b which displayed IC50 < 0.2 μM. No significant cytotoxicity was noted on the L-6 rat cell line. Moreover, in vivo studies suggested that compound 3b 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.

Molecular hybrids of substituted phenylcarbamoylpiperidine and 1,2,4-triazole methylacetamide as potent 15-LOX inhibitors: Design, synthesis, DFT calculations and molecular docking studies

Inflammation is a multifaceted phenomenon triggered by potentially active mediators acutely released arachidonic acid metabolites partially in lipoxygenase (LOX) pathway which are primarily accountable for causing several diseases in humans. It is widely believed that an inhibitor of the LOX pathway represents a rational approach for designing more potent antiinflammatory leads with druggable super safety profiles. In our continual efforts in search for anti-LOX molecules, the present work was to design a new series of N-alkyl/aralkyl/aryl derivatives (7a-o) of 4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,2,4-triazole-3-thiol which was commenced in seriate formation of phenylcarbamoyl derivative (1), hydrazide (2), semicarbazide (3) and 4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,2,4-triazole-3-thiol (4). The aimed compounds were obtained by reacting 4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,2,4-triazole-3-thiol with assorted N-alkyl/aralkyl/aryl electrophiles. All compounds were characterized by FTIR, 1H-, 13C-NMR spectroscopy, EI-MS and HR-EI-MS spectrometry and screened against soybean 15-LOX for their inhibitory potential using chemiluminescence method. All the compounds except 7m and 7h inhibited the said enzyme remarkably. Compounds 7c,7l, 7j and 7a displayed potent inhibitions ranging from IC50 1.92 ± 0.13 µM to 7.65 ± 0.12 µM. Other analogues 7g, 7o, 7e, 7b, 7d, 7k and 7n revealed excellent inhibitory values ranging from IC50 12.45 ± 0.38 µM to 24.81 ± 0.47 µM. All these compounds did not reveal DPPH radical scavenging activity. Compounds 7i-o maintained > 90 % human blood mononuclear cells (MNCs) viability at 0.125 mM as assayed by MTT whilst others were found toxic. Pharmacokinetic profiles predicted good oral bioavailability and drug-likeness properties of the active scaffolds. SAR investigations showed that phenyl substituted analogue on amide side decreased inhibitory activity due to inductive and mesomeric effects while the mono-alkyl substituted analogues were more active than disubstituted ones and ortho substituted analogues were more potent than meta substituted ones. MD simulation predicted the stability of the 7c ligand and receptor complex as shown by their relative RMSD (root mean square deviation) values. Molecular docking studies displayed hydrogen bonding between the compounds and the enzyme with Arg378 which was common in 7n, 7g, 7h and baicalein. In 7a and quercetin, hydrogen bonding was established through Asn375. RMSD values exhibited good inhibitory profiles in the order quercetin (0.73 Å) < 7 g < baicalein < 7a < 7n < 7 h (1.81 Å) and the binding free energies followed similar pattern. Density functional theory (DFT) data established good correlation between the active compounds and significant activity was associated with more stabilized LUMO (lowest unoccupied molecular orbitals) orbitals. Nevertheless, the present studies declare active analogues like 7c, 7 l, 7a, 7j as leads. Work is ongoing in derivatizing active molecules to explore more effective leads as 15-LOX inhibitors as antiinflammatory agents.

Novel dihydrobenzofuran derivatives: design, synthesis, cytotoxic activity, apoptosis, molecular modelling and DNA binding studies

Pyrazoline derivatives (3a–3e) and (4a–4e) were designed and synthesized through chalcones (2a–2e) cyclization with NH2NH2/HCOOH and NH2CSNHNH2/CH3COOH, respectively. The molecular structures were elucidated by using various techniques such as UV–visible, FT-IR, 1H, 13C NMR spectroscopy and mass spectrometry. The purity of all synthesized compounds was checked by the liquid chromatography–mass spectrometry (LC–MS). Single X-ray crystallography was confirmed the molecular structure of analogs (2d, 3e and 4e). Anticancer activity of the all derivatives was screened against human cancer cell MCF-7 and HepG2 cell lines by MTT assay. The results of anticancer activity of novel analogs 2b, 3b and 3e exhibited promising activity against MCF-7 but low toxic against the HepG2 normal cell line. By using a flow cytometry-based technique, the anticancer effectiveness of potent compounds against the MCF-7 cancer cell line was further validated. DNA binding interactions of the novel analogs 3b and 3e were carried out with calf thymus DNA (Ct-DNA) using absorption, fluorescence, circular dichroism and cyclic voltammetry. In silico molecular modelling of pyrazoline derivatives were also studied using Schrödinger-Maestro v2021-2 against tyrosine kinase receptor with PDB ID: 1M17 to explore their best hits. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical was used to measure the antioxidant capacity of active pyrazoline derivatives. Using Swiss ADMET software, the ADMET characteristics of pyrazoline derivatives were also investigated. Communicated by Ramaswamy H. Sarma