In vitro and in silico insights into the molecular interaction mechanism of acetylshikonin with bovine serum albumin

A novel macrolactam named oxalactam A (1), three known dipeptides (2–4) as well as other known alkaloids (5–7) were obtained from the endophytic fungus Penicillium oxalicum, which was derived from the tuber of Icacina trichantha (Icacinaceae). All chemical structures were established based on spectroscopic data, chemical methods, ECD calculations, and 13C-DP4+ analysis. Among them, oxalactam A (1) is a 16-membered polyenic macrolactam bearing a new skeleton of 2,9-dimethyl-azacyclohexadecane core and exhibited potent anti-Rhizoctonia solani activity with a MIC value of 10 μg/mL in vitro. The plausible biosynthetic pathway of 1 was also proposed via the alanyl protecting mechanism. Notably, three dipeptides (2–4) were first identified from the endophytic fungus P. oxalicum and the NMR data of cyclo(L-Trp-L-Glu) (2) was reported for the first time. In addition, the binding interactions between compound 1 and the sterol 14α-demethylase enzyme (CYP51) were studied by molecular docking and dynamics technologies, and the results revealed that the 16-membered polyenic macrolactam could be a promising CYP51 inhibitor to develop as a new anti-Rhizoctonia solani fungicide.

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Oxalactam A, a Novel Macrolactam with Potent Anti-Rhizoctonia solani Activity from the Endophytic Fungus Penicillium oxalicum

By exploiting the ample biological potential of 1,3,4-oxadiazole/thiadiazole ring, 4-substitutedphenyl-1,3,4-oxadiazol/Thiadiazol-2-yl)-4-(4-substitutedphenyl) azetidin-2-one derivatives were prepared. Various substituted azetidin-2-one derivatives have been identified as immunostimulating and antimicrobial, as well as their antioxidant activity. 2-amino 1,3,4 oxadiazole/thiadiazole conjugates were synthesized by mixing semi/thio carbazides and sodium acetate with water and stirring well, followed by adding aldehydes in methanol at room temperature. Acetate (glacial) was used as the catalyst to produce Schiff’s bases (intermediates) by treating substituted aldehydes with 2-amino 1,3,4 oxadiazole/thiadiazole(s). Using the mixture of triethylamine (dropwise) and chloroacetylchloride with vigorous stirring, 4-substitutedphenyl-1,3,4-oxadiazol/Thiadiazol-2-yl)-4-(4-substitutedphenyl) azetidin-2-one derivatives were prepared. The newly synthesized conjugates were evaluated for their anticancer potential using MCF-7 cell lines. Amoxicillin and fluconazole were used as reference drugs to determine their antimicrobial activity. Synthesized derivatives were evaluated for their antioxidant properties using 2-diphenyl-1-picrylhydrazyl (DPPH). In vitro cytotoxicity screening (MTTS assay) revealed that derivatives AZ-5, 9, 10, 14 and 19 demonstrated high efficacy with the percentage of inhibition at different concentration ranges (0.1 μM, 0.5 μM, 1 μM, 2 μM) of 89% to 94% μM as compared to doxorubicin as standard drug. The antimicrobial study indicated that compounds AZ-10, 19, and AZ-20 were found to have significant antimicrobial potential with MIC ranges of 3.34 µM to 3.71 µM in comparison to reference drugs having 4.29 µM to 5.10 µM. Based on antioxidant screening, most of the synthetic derivatives showed greater stability and effectiveness than the standard drug. According to the antioxidant screening, compounds AZ-5 and AZ-15 (IC50 = 45.02 μg/mL and 42.88 μg/mL, respectively) showed the greatest potency, as compared to ascorbic acid (IC50 = 78.63 μg/mL). Structure-activity relationship (SAR) studies of synthesized novel derivatives revealed that para-substituted halogen and nitro derivatives have remarkable potential against MCF-7 cancer cell lines and different microbial strains. Current evidence indicates that the synthesized derivatives may be promising candidates for use in the prevention and treatment of these infections. These synthesized compounds require further mechanism-based research to understand how they interact with the cells.

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Synthesis, Anticancer, Antimicrobial and Antioxidant Potential of Novel 4-(Substituted phenyl-1,3,4-oxadiazol/thiadiazol-2-yl)-4-(4-substituted phenyl) Azetidin-2-One Derivatives

The world’s health system is plagued by cancer and a worldwide effort is underway to find new drugs to treat cancer. There has been a significant improvement in understanding the pathogenesis of cancer, but it remains one of the leading causes of death. The imperative 1,3,4-oxadiazole scaffold possesses a wide variety of biological activities, particularly for cancer treatment. In the development of novel 1,3,4-oxadiazole-based drugs, structural modifications are important to ensure high cytotoxicity towards malignant cells. These structural modification strategies have shown promising results when combined with outstanding oxadiazole scaffolds, which selectively interact with nucleic acids, enzymes, and globular proteins. A variety of mechanisms, such as the inhibition of growth factors, enzymes, and kinases, contribute to their antiproliferative effects. The activity of different 1,3,4-oxadiazole conjugates were tested on the different cell lines of different types of cancer. It is demonstrated that 1,3,4-oxadiazole hybridization with other anticancer pharmacophores have different mechanisms of action by targeting various enzymes (thymidylate synthase, HDAC, topoisomerase II, telomerase, thymidine phosphorylase) and many of the proteins that contribute to cancer cell proliferation. The focus of this review is to highlight the anticancer potential, molecular docking, and SAR studies of 1,3,4-oxadiazole derivatives by inhibiting specific cancer biological targets, such as inhibiting telomerase activity, HDAC, thymidylate synthase, and the thymidine phosphorylase enzyme. The purpose of this review is to summarize recent developments and discoveries in the field of anticancer drugs using 1,3,4-oxadiazoles.

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An Understanding of Mechanism-Based Approaches for 1,3,4-Oxadiazole Scaffolds as Cytotoxic Agents and Enzyme Inhibitors

Dichloroacetate (DCA) is considered as a highly bioavailable and small anticancer agent which reduces tumor growth through inhibition of pyruvate dehydrogenase kinases. Various DCA derivatives were designed, synthesized and eluated by FT-IR, 1HNMR, 13CNMR and Mass spectrum. Biological evaluations of the synthesized compounds were evaluated against three human cancer cell lines, A549 (lung), MCF-7 (breast), and MDA-MB-231 (breast), as well as a non-tumorigenic breast cell line (MCF-10A). Among synthesized compounds, N-(2-(tert-butylamino)-1-(4-nitrophenyl)-2-oxoethyl)-2,2-dichloro-N-(2-fluorophenyl)acetamide (A5) had a promising cytotoxic effect with IC50 values of 11.94, 15.57, and 16.54 μM against MCF-7, MDA-MB-231, and A549 cells, respectively. It can also induce apoptosis in MCF-7 cell line. Molecular docking and molecular dynamic simulation studies were also carried out show binding sites and energies to the PDKs isoenzymes. All of the compounds demonstrated appropriate selectivity between cancerous and non-cancerous cell lines. These results provide valuable insight for the additional development of novel dichloroacetate-containing compounds. 

Synthesis of N‐(2‐(tert‐Butylamino)‐2‐oxoethyl)‐2,2‐dichloro‐N‐aryl(alkyl)acetamides as Anticancer Agents: Molecular Modeling and Biological Evaluations

1,3,4-Oxadiazole as an emerging telomerase inhibitor - a promising anticancer motif

In order to explore new antifungal agrochemicals, we reported the synthesis of two series 5a–f, 6 and 7a–f, 8 of benzothiazole-appended bis-triazole derivative-based structural isomers using a molecular hybridization approach. The synthesized compounds were tested for fungal growth inhibition against the plant pathogen Rhizoctonia solani. All the synthesized compounds showed excellent antifungal activity in their minimum concentrations (10–0.62 μM). Among all the synthetics, compounds 5b (ED50: 2.33 μM), 5f (ED50: 0.96 μM), and 7f (ED50: 1.48 μM) exerted a superior inhibitory effect in comparison to the commercially available fungicide, hexaconazole (ED50: 2.44 μM). The binding interactions of the active compounds 5f, 7f, 6, and 8 within the active site of the sterol 14α-demethylase enzyme were studied with the help of molecular docking studies. The studies revealed that these hybrid pharmacophores could be used as an important intermediate to demonstrate new structural isomer-based fungicides.

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Synthesis of benzothiazole-appended bis-triazole-based structural isomers with promising antifungal activity against Rhizoctonia solani

Scrutinzing the Interaction of Bovine Serum Albumin and Human Hemoglobin with Isatin-triazole Functionalized Rhodamine through Spectroscopic and In-silico Approaches

In our effort directed toward the discovery of novel potent anticancer agents, a large library of novel 4-aryl-1,4-dihydropyridines (23-58) with heterocyclic ring at 4, position of aryl group has been synthesized through Hantzsch synthesis. These synthesized hybrids have been well characterized and evaluated for their cytotoxic activities against a panel of human cancer cell lines viz. EAC, HEK, and MCF cell lines by MTT assay. The cytotoxic activity has been revealed by the effects of various types of substituent present on the dihydropyridine ring. All the synthetics (23-58) have shown good potency against EAC cell line. However, compounds 36, 40, 42, and 54 have displayed significant inhibitory potential against both EAC and MCF-7 cell lines. In addition, these promising analogues have been selected for their molecular docking studies against 5TVQ protein to know the binding affinity which was identified to be a plausible target site. Compound 42 has exerted the highest inhibition effect on cancerous cells and more potency than the reference drug, doxorubicin even at low concentration (1μg/ml) and showed non-toxicity to human normal cells suggesting high safety to normal cells. Compound 42 has also shown the highest docking score and inhibition constant which could be regarded as convincing lead for further clinical pursuit. 

Microwave‐Assisted Synthesis of 4‐Aryl‐1,4‐dihydropyridines as Potent Anticancer Agent and Their
 In‐Silico Studies

A pyridine dicarboxylate Schiff-base DAS was synthesized for cascade colorimetric recognition of Ni2+ and PPi. The selectivity and sensitivity of chemosensor DAS was investigated through colorimetric and UV-vis studies in MeOH-PBS (5 : 1, v/v, pH = 7.4). The chemosensor formed a 2 : 1 complex with Ni2+ metal ions with a binding constant of Ka = 3.07 × 103 M−2. Besides, a plausible sensing mechanism is confirmed by single crystal X-ray diffraction (SC-XRD), Job's plot and Benesi–Hildebrand plot (B–H plot) experiments. Furthermore, the DAS-Ni2+ ensemble formed ‘in situ’ was used to selectively recognise PPi. The limit of detection (LOD) of DAS for Ni2+ was found to be 0.14 μM and that of the DAS-Ni2+ ensemble for PPi was found to be 0.33 μM. Also, the potential of the chemosensor has been applied for solid state detection of Ni2+ as well as to mimic the ‘INHIBIT’ logic gate on the addition of Ni2+ ions and PPi.

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Rakesh Kumar

Papers

1,3,4-Oxadiazole as an emerging telomerase inhibitor - a promising anticancer motif

Synthesis of benzothiazole-appended bis-triazole-based structural isomers with promising antifungal activity against Rhizoctonia solani

Scrutinzing the Interaction of Bovine Serum Albumin and Human Hemoglobin with Isatin-triazole Functionalized Rhodamine through Spectroscopic and In-silico Approaches

Microwave‐Assisted Synthesis of 4‐Aryl‐1,4‐dihydropyridines as Potent Anticancer Agent and Their In‐Silico Studies

A pyridine dicarboxylate based hydrazone Schiff base for reversible colorimetric recognition of Ni2+ and PPi