Facile synthesis of substituted 2-aroylbenzo[b]thiophen-3-ols to form novel triazole hybrids using click chemistry.

An efficient one-pot method is proposed for the synthesis of 2-aroylbenzo[b]thiophen-3-ols from 2-mercaptobenzoic acid and various substituted aryl bromomethyl ketones in the presence of triethylamine. The reaction is likely to proceed through SN2-type nucleophilic attack of the sulfhydryl group in thiosalicylic acid on bromomethyl ketone in the presence of a base to afford sulfanylbenzoic acid, which undergoes an intramolecular cyclization in situ to furnish 2-aroylbenzo[b]thiophen-3-ol in high yield. To investigate the utility of the synthesized benzothiophene scaffold, an alkyne moiety was introduced at the 3-hydroxy position and subsequently subjected to a click reaction to form novel benzothiophene-triazole hybrids in good yields. A simple and straightforward approach to synthesizing 2-aroylbenzo[b]thiophen-3-ols can open new avenues for discovering novel biological and pharmaceutical compounds.

Cocrystals of a coumarin derivative: an efficient approach towards anti-leishmanial cocrystals against MIL-resistant Leishmania tropica.

Leishmaniasis is a neglected parasitic tropical disease with numerous clinical manifestations. One of the causative agents of cutaneous leishmaniasis (CL) is Leishmania tropica (L. tropica) known for causing ulcerative lesions on the skin. The adverse effects of the recommended available drugs, such as amphotericin B and pentavalent antimonial, and the emergence of drug resistance in parasites, mean the search for new safe and effective anti-leishmanial agents is crucial. Miltefosine (MIL) was the first recommended oral medication, but its use is now limited because of the rapid emergence of resistance. Pharmaceutical cocrystallization is an effective method to improve the physicochemical and biological properties of active pharmaceutical ingredients (APIs). Herein, we describe the cocrystallization of coumarin-3-carboxylic acid (CU, 1a; 2-oxobenzopyrane-3-carboxylic acid, C10H6O4) with five coformers [2-amino-3-bromopyridine (1b), 2-amino-5-(trifluoromethyl)-pyridine (1c), 2-amino-6-methylpyridine (1d), p-aminobenzoic acid (1e) and amitrole (1f)] in a 1:1 stoichiometric ratio via the neat grinding method. The cocrystals 2-6 obtained were characterized via single-crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis, as well as Fourier transform infrared spectroscopy. Non-covalent interactions, such as van der Waals, hydrogen bonding, C-H...π and π...π interactions contribute significantly towards the packing of a crystal structure and alter the physicochemical and biological activity of CU. In this research, newly synthesized cocrystals were evaluated for their anti-leishmanial activity against the MIL-resistant L. tropica and cytotoxicity against the 3T3 (normal fibroblast) cell line. Among the non-cytotoxic cocrystals synthesized (2-6), CU:1b (2, IC50 = 61.83 ± 0.59 µM), CU:1c (3, 125.7 ± 1.15 µM) and CU:1d (4, 48.71 ± 0.75 µM) appeared to be potent anti-leishmanial agents and showed several-fold more anti-leishmanial potential than the tested standard drug (MIL, IC50 = 169.55 ± 0.078 µM). The results indicate that cocrystals 2-4 are promising anti-leishmanial agents which require further exploration.

Synthesis and Characterization of New Spirooxindoles Including Triazole and Benzimidazole Pharmacophores via [3+2] Cycloaddition Reaction: An MEDT Study of the Mechanism and Selectivity.

A new series of spirooxindoles based on benzimidazole, triazole, and isatin moieties were synthesized via a [3+2] cycloaddition reaction protocol in one step. The single X-ray crystal structure of the intermediate triazole-benzimidazole 4 was solved. The new chemical structures of these spirooxindole molecules have been achieved for the first time. The final synthesized chemical architecture has differently characterized electronic effects. An MEDT study of the key 32CA reaction between in situ generated azomethine ylide (AY) and chalcones explained the low reaction rates and the total selectivities observed. The supernucleophilic character of AY and the strong electrophilicity of chalcones favor these reactions through a highly polar two-stage one-step mechanism in which bond formation at the ß-conjugated carbon of the chalcones is more advanced. The present combined experimental and theoretical study reports the synthesis of new spirooxindoles with potential biological activities and fully characterizes the molecular mechanisms for their formation through the key 32CA reaction step.

New cocrystals of heterocyclic drugs: structural, antileishmanial, larvicidal and urease inhibition studies.

Many heterocycles have been developed as drugs due to their capacity to interact productively with biological systems. The present study aimed to synthesize cocrystals of the heterocyclic antitubercular agent pyrazinamide (PYZ, 1, BCS III) and the commercially available anticonvulsant drug carbamazepine (CBZ, 2, BCS class II) to study the effect of cocrystallization on the stability and biological activities of these drugs. Two new cocrystals, namely, pyrazinamide-homophthalic acid (1/1) (PYZ:HMA, 3) and carbamazepine-5-chlorosalicylic acid (1/1) (CBZ:5-SA, 4), were synthesized. The single-crystal X-ray diffraction-based structure of carbamazepine-trans-cinnamic acid (1/1) (CBZ:TCA, 5) was also studied for the first time, along with the known cocrystal carbamazepine-nicotinamide (1/1) (CBZ:NA, 6). From a combination drug perspective, these are interesting pharmaceutical cocrystals to overcome the known side effects of PYZ (1) therapy, and the poor biopharmaceutical properties of CBZ (2). The purity and homogeneity of all the synthesized cocrystals were confirmed by single-crystal X-ray diffraction, powder X-ray diffraction and FT-IR analysis, followed by thermal stability studies based on differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Detailed intermolecular interactions and the role of hydrogen bonding towards crystal stability were evaluated quantitatively via Hirshfeld surface analysis. The solubility of CBZ at pH 6.8 and 7.4 in 0.1 N HCl and H2O were compared with the values of cocrystal CBZ:5-SA (4). The solubility of CBZ:5-SA was found to be significantly improved at pH 6.8 and 7.4 in H2O. All the synthesized cocrystals 3-6 exhibited a potent urease inhibition (IC50 values range from 17.32 ±â€…0.89 to 12.3 ±â€…0.8 µM), several times more potent than standard acetohydroxamic acid (IC50 = 20.34 ±â€…0.43 µM). PYZ:HMA (3) also exhibited potent larvicidal activity against Aedes aegypti. Among the synthesized cocrystals, PYZ:HMA (3) and CBZ:TCA (5) were found to possess antileishmanial activity against the miltefosine-induced resistant strain of Leishmania major, with IC50 values of 111.98 ±â€…0.99 and 111.90 ±â€…1.44 µM, respectively, in comparison with miltefosine (IC50 = 169.55 ±â€…0.20 µM).

Optimized spirooxindole-pyrazole hybrids targeting the p53-MDM2 interplay induce apoptosis and synergize with doxorubicin in A549 cells.

Recently, cancer research protocols have introduced clinical-stage spirooxindole-based MDM2 inhibitors. However, several studies reported tumor resistance to the treatment. This directed efforts to invest in designing various combinatorial libraries of spirooxindoles. Herein, we introduce new series of spirooxindoles via hybridization of the chemically stable core spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one and the pyrazole motif inspired by lead pyrazole-based p53 activators, the MDM2 inhibitor BI-0252 and promising molecules previously reported by our group. Single crystal X-ray diffraction analysis confirmed the chemical identity of a representative derivative. Fifteen derivatives were screened for cytotoxic activities via MTT assay against a panel of four cancer cell lines expressing wild-type p53 (A2780, A549, HepG2) and mutant p53 (MDA-MB-453). The hits were 8h against A2780 (IC50 = 10.3 µM) and HepG2 (IC50 = 18.6 µM), 8m against A549 (IC50 = 17.7 µM), and 8k against MDA-MB-453 (IC50 = 21.4 µM). Further MTT experiments showed that 8h and 8j potentiated doxorubicin activity and reduced its IC50 by at least 25% in combinations. Western blot analysis demonstrated that 8k and 8m downmodulated MDM2 in A549 cells. Their possible binding mode with MDM2 were simulated by docking analysis.

Synthesis, DNA binding and biological evaluation of benzimidazole Schiff base ligands and their metal(ii) complexes.

Two novel benzimidazole ligands (E)-2-((4-(1H-benzo[d]imidazole-2-yl)phenylimino)methyl)-6-bromo-4-chlorophenol (L1) and (E)-1-((4-(1H-benzo[d]imidazole-2-yl)phenylimino)methyl)naphthalene-2-ol (L2) with their corresponding Cu(ii), Ni(ii), Pd(ii) and Zn(ii) complexes were designed and synthesized. The compounds were characterized by elemental, IR, and NMR (1H & 13C) spectral analyses. Molecular masses were determined by ESI-mass spectrometry, and the structure of ligand L1 was confirmed by single crystal X-ray diffraction analysis. Molecular docking was carried out for the theoretical investigation of DNA binding interactions. The results obtained were verified experimentally by UV/Visible absorption spectroscopy in conjunction with DNA thermal denaturation studies. It was observed that ligands (L1 and L2) and complexes (1-8) were moderate to strong DNA binders, as evident from the binding constants (K b). The value was found to be highest for complex 2 (3.27 × 105 M-1) and lowest for 5 (6.40 × 103 M-1). A cell line study revealed that breast cancer cells were less viable to the synthesized compounds compared to that of standard drugs, cisplatin and doxorubicin, at the same concentration. The compounds were also screened for in vitro antibacterial activity for which complex 2 showed a promising broad-spectrum effect against all tested strains of bacteria, almost in the proximity of the reference drug kanamycin, while the rest of the compounds displayed activity against selected strains.

Physico-Chemical Properties of Magnetic Dicationic Ionic Liquids with Tetrahaloferrate Anions.

A series of imidazolium-based symmetrical and asymmetrical dicationic ionic liquids (DcILs) with alkyl spacers of different length and with [FeCl3 Br]- as counter ion have been synthesized. The synthesized DcILs are characterized by using FTIR and Raman spectroscopy as well as mass spectrometry, along with single-crystal XRD analysis. Physicochemical properties such as solubility, thermal stability and magnetic susceptibility are also measured. These compounds show low melting points, good solubility in water and organic solvents, thermal stability, and paramagnetism. The products of molar susceptibility and temperature (χmol ⋅T) for the synthesized DcILs have been found between 4.05 to 4.79 emu mol-1 K Oe-1 and effective magnetic moment values have also been determined to be compared to that expected from the spin-only approximation.

Anti-leishmanial physalins-Phytochemical investigation, in vitro evaluation against clinical and MIL-resistant L. tropica strains and in silico studies.

Cutaneous leishmaniasis (CL) is a major health problem in over 98 countries of the world, including Pakistan. The current treatments are associated with a number of adverse effects and availability problem of drugs. Therefore, there is an urgent need of easily available and cost effective treatments of CL- in Pakistan. The bioassay-guided fractionation and purification of crude extract of Physalis minima has led to the isolation of a new aminophysalin B (1), and eight known physalins, physalin B (2), 5ß,6ß-epoxyphysalin B (3), 5α-ethoxy-6ß-hydroxy-5,6-dihydrophysalin B (4), physalin H (5), 5ß,6ß-epoxyphysalin C (6), and physalin G (7), K (8), and D (9). It is worth noting that compound 1 is the second member of aminophysalin series, whereas compound 6 was fully characterized for the first time. The structures of compounds 1-9 were elucidated by spectroscopic techniques Whereas, the structural assignments of compounds 1 and 8 were also supported by single-crystal X-ray diffraction studies. The anti-leishmanial activity of isolated physlains 1-9 was evaluated against Leishmania major and Leishmania tropica promastigotes. Compounds 2, 3, and 5-7 (IC50 = 9.59 ± 0.27-23.76 ± 1.10 µM) showed several-fold more potent activity against L. tropca than tested drug miltefosine (IC50 = 42.75 ± 1.03 µm) and pentamidine (IC50 = 27.20 ± 0.01 µM). Whereas compounds 2, 3 and 5 (IC50 = 3.04 ± 1.12-3.76 ± 0.85 µM) were found to be potent anti-leishmanial agents against L. major, several fold more active than tested standard miltefosine (IC50 = 25.55 ± 1.03 µM) and pentamidine (IC50 = 27.20 ± 0.015 µM). Compounds 4 (IC50 = 74.65 ± 0.81 µM) and 7 (IC50 = 39.44 ± 0.65 µM) also showed potent anti-leishmanial ativity against the miltefosine-unresponsive L. tropica strain (MIL resistant) (miltefosine IC50 = 169.55 ± 0.78 µM). Molecular docking and predictive binding studies indicated that these inhibitors may act via targeting important enzymes of various metabolic pathways of the parasites.

Antileishmanial Activities of (Z)-2-(Nitroimidazolylmethylene)-3(2H)-Benzofuranones: Synthesis, In Vitro Assessment, and Bioactivation by NTR 1 and 2.

The antileishmanial activity of a series of (Z)-2-(heteroarylmethylene)-3(2H)-benzofuranone derivatives, possessing 5-nitroimidazole or 4-nitroimidazole moieties, was investigated against Leishmania major promastigotes and some analogues exhibited prominent activities. Compounds with IC50 values lower than 20 µM were further examined against L. donovani axenic amastigotes. Evaluated analogues in 5-nitroimidazole subgroup demonstrated significantly superior activity (~17-88-folds) against L. donovani in comparison to L. major. (Z)-7-Methoxy-2-(1-methyl-5-nitroimidazole-2-ylmethylene)-3(2H)-benzofuranone (5n) showed the highest L. donovani anti-axenic amastigote activity with IC50 of 0.016 µM. The cytotoxicity of these analogues was determined using PMM peritoneal mouse macrophage and THP-1 human leukemia monocytic cell lines and high selectivity indices of 26 to 431 were obtained for their anti-axenic amastigote effect over the cytotoxicity on PMM cells. Further studies on their mode of action showed that 5-nitroimidazole compounds were bioactivated predominantly by nitroreductase 1 (NTR1) and 4-nitroimidazole analogues by both NTR1 and 2. It is likely that this bioactivation results in the production of nitroso and hydroxylamine metabolites that are cytotoxic for the Leishmania parasite.

Reassessing the molecular structures of some previously isolated abietane diterpenoids with a naphthalene moiety and the structure-activity relationship (SAR) of quinone diterpenoids.

Crystals of previously described para-naphthoquinone abietane diterpenoids 12,16-dideoxy-aegyptinone B and 12-deoxy-salvipisone were obtained from Zhumeria majdae Rech.f. & Wendelbo. However, single-crystal X-ray diffraction analysis followed by reinterpretation of their NMR data revealed that their structures require revision, and they should be revised to the two ortho-naphthoquinones, zhumerianone C and aethiopinone, respectively. Interestingly, a further search through literature revealed that there were more of such cases, in which differentiation between the ortho-/para-orientation had not been carried out correctly in the structure elucidation of naphthalene containing abietane diterpenoids. Therefore, in the current study, we pointed out some 1D and 2D NMR generalizations that would help the unambiguous deduction of the ortho-/para-orientation of naphthalene containing abietanes and revised the structure of some previously described compounds accordingly. Based on these generalizations, structures of sibiriquinones A and B, sahandinone, and sahandone were revised to the known structures 1,2-didehydromiltirone, miltirone, saprorthoquinone, and sahandone B, respectivelyand tebesinone B, arucadiol, and sahandol II were revised to three undescribed structures. It was also proposed that structures of palmitoyl arucadiol and compounds with the salvifolane skeleton need revision. Furthermore, these structure revisions shed light on the structure-activity relationship of the quinone diterpenoids, approving that the ortho-quinone is the critical structural component for cytotoxicity in these compounds.

Isolation, derivatization, in-vitro, and in-silico studies of potent butyrylcholinesterase inhibitors from Berberis parkeriana Schneid.

Seven known isoquinoline alkaloids 1-7 were isolated from the root extracts of Berberis parkeriana Schneid. Nine new derivatives 8-16 of one of the isolated compounds, jatrorrhizine (7), were synthesized. All the isolated as well as derivatized compounds were evaluated for their in-vitro acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activity. Functionalized compounds selectively exhibited a potent-to-moderate activity with IC50 = 5.5 ± 0.3-124.5 ± 0.4 µM against butyrylcholinesterase enzyme. Among them, compound 15 was a potent BChE inhibitor (IC50 = 5.5 ± 0.3 µM), as compared to the standard drug galantamine hydrobromide (IC50 = 40.83 ± 0.37 µM). Active compounds were further subjected to kinetic, and molecular docking studies to predict their modes of inhibition, and interactions with the receptor (BChE), respectively. Enzyme kinetics studies showed that compounds 9 (IC50 = 25.3 ± 0.5 µM), and 14 (IC50 = 23.9 ± 0.5 µM) were non-competitive inhibitors, while compound 15 exhibited a competitive inhibition. In addition, these compounds were found to be non-cytotoxic against human fibroblast (BJ) cell line, except 9 (IC50 = 17.1 ± 1.0 µM), and 10 (IC50 = 18.4 ± 0.3 µM). Inhibition of cholinesterases is an important approach for development of drugs against Alzheimer's disease, and thus discoveries presented here deserve further investigation.

A new bioactive cocrystal of coumarin-3-carboxylic acid and thiourea: detailed structural features and biological activity studies.

Cocrystallization is a phenomenon widely used to enhance the biological and physicochemical properties of active pharmaceutical ingredients (APIs). The present study deals with the synthesis of a cocrystal of coumarin-3-carboxylic acid (2-oxochromene-3-carboxylic acid, C10H6O4), a synthetic analogue of the naturally occurring antioxidant coumarin, with thiourea (CH4N2S) using the neat grinding method. The purity and homogeneity of the coumarin-3-carboxylic acid-thiourea (1/1) cocrystal was confirmed by single-crystal X-ray diffraction, FT-IR analysis and thermal stability studies based on differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Detailed geometry analysis via density functional theory (DFT) demonstrated that the 1:1 cocrystal stoichiometry is sustained by N-H...O hydrogen bonding between the amine (-NH2) groups of thiourea and the carbonyl group of coumarin. The synthesized cocrystal exhibited potent antioxidant activity (IC50 = 127.9 ± 5.95 µM) in a DPPH radical scavenger assay in vitro in comparison with the standard N-acetyl-L-cysteine (IC50 = 111.6 ±â€…2.4 µM). The promising results of the present study highlight the significance of cocrystallization as a crystal engineering tool to improve the efficacy of pharmaceutical ingredients.

Microwave assisted Biology-Oriented Drug Synthesis (BIODS) of new N,N'-disubstituted benzylamine analogous of 4-aminoantipyrine against leishmaniasis - In vitro assay and in silico-predicted molecular interactions with key metabolic targets.

Biology-Oriented Drug Synthesis (BIODS) deals with the simple chemical transformations on the commercially available drugs in order to enhance their new and diversified pharmacological profile. It opens new avenues for the rapid development of drug candidates for neglected tropical diseases (NTDs). Leishmaniasis is one of the NTDs which spread by the bite of sandflies (plebotomine). It ranges from cutaneous self-healing leishmaniasis to life threatening visceral leishmaniasis, known as kala-azar. The current treatment options include the use of pentamidine, miltefosine, and amphotericin B drugs. Unfortunately, all currently available drugs are associated with adverse effects, such as severe nephron- and cardiotoxicity, pancreatitis, and hepatotoxicity. This warrants the development of new drugs against leishmaniasis. Moreover, emergence of resistance against the current medications further worsens the conditions. With this objective, new N, N'-disubstituted benzylamine derivatives of ampyrone (4-aminoantipyrine) were synthesized by using ultrasonication, and microwave assistance. All derivatives were found to be new, except 1, 4, and 11. All the compounds were evaluated for their anti-leishmanial activity, and cellular cytotoxicity. Among them, compounds 4, 5, 8, and 9 showed a significant anti-leishmanial activity in vitro, in comparison to standard drug, miltefosine (IC50 = 25.78 ± 0.2 µM). These compounds were also docked against various metabolic enzymes to predict their interactions and mechanism of action, and were found to act via targeting important enzymes of various metabolic pathways.

Design, Synthesis, Chemical and Biochemical Insights Into Novel Hybrid Spirooxindole-Based p53-MDM2 Inhibitors With Potential Bcl2 Signaling Attenuation.

The tumor resistance to p53 activators posed a clinical challenge. Combination studies disclosed that concomitant administration of Bcl2 inhibitors can sensitize the tumor cells and induce apoptosis. In this study, we utilized a rapid synthetic route to synthesize two novel hybrid spirooxindole-based p53-MDM2 inhibitors endowed with Bcl2 signaling attenuation. The adducts mimic the thematic features of the chemically stable potent spiro [3H-indole-3,2'-pyrrolidin]-2(1H)-ones p53-MDM2 inhibitors, while installing a pyrrole ring via a carbonyl spacer inspired by the natural marine or synthetic products that efficiently inhibit Bcl2 family functions. A chemical insight into the two synthesized spirooxindoles including single crystal x-ray diffraction analysis unambiguously confirmed their structures. The synthesized spirooxindoles 2a and 2b were preliminarily tested for cytotoxic activities against normal cells, MDA-MB 231, HepG-2, and Caco-2 via MTT assay. 2b was superior to 5-fluorouracil. Mechanistically, 2b induced apoptosis-dependent anticancer effect (43%) higher than that of 5-fluorouracil (34.95%) in three studied cancer cell lines, activated p53 (47%), downregulated the Bcl2 gene (1.25-fold), and upregulated p21 (2-fold) in the treated cancer cells. Docking simulations declared the possible binding modes of the synthesized compounds within MDM2.

Stereoselective Synthesis of the Di-Spirooxindole Analogs Based Oxindole and Cyclohexanone Moieties as Potential Anticancer Agents.

A new series of di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were synthesized. Initially, azomethine ylides were generated via reaction of the substituted isatins 3a-f (isatin, 3a, 6-chloroisatin, 3b, 5-fluoroisatin, 3c, 5-nitroisatin, 3d, 5-methoxyisatin, 3e, and 5-methylisatin, 3f, and (2S)-octahydro-1H-indole-2-carboxylic acid 2, in situ azomethine ylides reacted with the cyclohexanone based-chalcone 1a-f to afford the target di-spirooxindole compounds 4a-n. This one-pot method provided diverse structurally complex molecules, with biologically relevant spirocycles in a good yields. All synthesized di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were evaluated for their anticancer activity against four cancer cell lines, including prostate PC3, cervical HeLa, and breast (MCF-7, and MDA-MB231) cancer cell lines. The cytotoxicity of these di-spirooxindole analogs was also examined against human fibroblast BJ cell lines, and they appeared to be non-cytotoxic. Compound 4b was identified as the most active member of this series against prostate cancer cell line PC3 (IC50 = 3.7 ± 1.0 µM). The cyclohexanone engrafted di-spirooxindole analogs 4a and 4l (IC50 = 7.1 ± 0.2, and 7.2 ± 0.5 µM, respectively) were active against HeLa cancer cells, whereas NO2 substituted isatin ring and meta-fluoro-substituted (2E,6E)-2,6-dibenzylidenecyclohexanone containing 4i (IC50 = 7.63 ± 0.08 µM) appeared to be a promising agent against the triple negative breast cancer MDA-MB231 cell line. To explore the plausible mechanism of anticancer activity of di-spirooxindole analogs, molecular docking studies were investigated which suggested that spirooxindole analogs potentially inhibit the activity of MDM2.

Bimetallic Iron-Palladium Catalyst System as a Lewis-Acid for the Synthesis of Novel Pharmacophores Based Indole Scaffold as Anticancer Agents.

The Friedel-Crafts reaction between substituted indoles as nucleophiles with chalcones-based benzofuran and benzothiophene scaffolds was carried out by employing a highly efficient bimetallic iron-palladium catalyst system. This catalytic approach produced the desired bis-heteroaryl products with low catalyst loading, a simple procedure, and with acceptable yield. All synthesized indole scaffolds 3a-3s were initially evaluated for their cytotoxic effect against human fibroblast BJ cell lines and appeared to be non-cytotoxic. All non-cytotoxic compounds 3a-3s were then evaluated for their anticancer activities against cervical cancer HeLa, prostate cancer PC3, and breast cancer MCF-7 cell lines, in comparison to standard drug doxorubicin, with IC50 values 1.9 ± 0.4 µM, 0.9 ± 0.14 µM and 0.79 ± 0.05 µM, respectively, and appeared to be moderate to weak anticancer agents. Fluoro-substituted chalcone moiety-containing compounds, 3b appeared to be the most active member of the series against cervical HeLa (IC50 = 8.2 ± 0.2 µM) and breast MCF-7 cancer cell line (IC50 = 12.3 ± 0.04 µM), whereas 6-fluroindol-4-bromophenyl chalcone-containing compound 3e (IC50 = 7.8 ± 0.4 µM) appeared to be more active against PC3 prostate cancer cell line.

Anticancer evaluation of a manganese complex on HeLa and MCF-7 cancer cells: design, deterministic solvothermal synthesis approach, Hirshfeld analysis, DNA binding, intracellular reactive oxygen species production, electrochemical characterization and density functional theory.

Herein, a deterministic solvothermal strategy was employed to synthesize an efficient anticancer agent 'cis-dichlorobis(1,10-phenanthroline)manganese(II)' (Mn(phen)2Cl2). A single-crystal X-ray diffraction analysis revealed that Mn(phen)2Cl2 crystallizes in a triclinic system with the space group P-1. Cyclic voltammetric studies of Mn(phen)2Cl2 indicated that the electrode process occurs only due to complex formation and has a diffusion-controlled mechanism. Density functional theory estimations showed that the Mn(phen)2Cl2 is quite stable and exists in sextet spin state (five unpaired electrons) as the most stable form and hence, Mn(phen)2Cl2 is a high spin complex. Mn(phen)2Cl2 demonstrated significant anticancer potential against HeLa and MCF-7 cancer cells and less toxic behaviour towards normal BHK-21 cells. Fluorescence imaging confirmed that the production of reactive oxygen species (ROS) in HeLa cells by Mn(phen)2Cl2 induces oxidized fluorescence of dichlorofluorescein which emitted fluorescence at 530 nm after excitation at 488 nm. The microscopic investigation of apoptotic effect of Mn(phen)2Cl2 using propidium iodide and 4',6-diamidino-2-phenylindole staining indicated that nuclear condensation, cell detachment and shrinkage occur after treatment with IC50 values of Mn(phen)2Cl2. Furthermore, an assessment of caspase-9 and caspase-3 activity after exposure to Mn(phen)2Cl2 in HeLa cells indicated that at IC50 values of Mn(phen)2Cl2, 1.5 fold and 4.8 fold increase in caspase-9 and caspase-3 activity, respectively, occurs. The measurement of mitochondrial membrane potential of a cationic dye (JC-1) showed a decrease in mitochondrial membrane potential in both HeLa and MCF-7 cells depicting that compound might have adopted intrinsic pathway of apoptosis. Ability of Mn(phen)2Cl2 to interact with HS-DNA demonstrates hyperchromicity with slight blue shift from 269 nm to 265 nm showing a non-covalent interaction with Gibbs free energy of ΔG = -14.62 kJ/mol. Communicated by Ramaswamy H. Sarma.

Celebrex derivatives: Synthesis, α-glucosidase inhibition, crystal structures and molecular docking studies.

Celebrex (1), commonly used as an anti-inflammatory drug, was functionalized (compounds 2-9) to identify new α-glucosidase inhibitors. Initially, all the synthesized derivatives were evaluated for anti-inflammatory activity but none was found to be active. Subsequently a random biological screening was carried out. Interestingly many of them were found to be potent α-glucosidase inhibitors in vitro. All the structures of synthesized derivatives were deduced through 1H NMR, FAB-MS, HR-MS, FT-IR analysis. The single-crystal X-ray structures of compounds 1, and 5 further confirmed the assigned structures. Compounds exhibited a potent α-glucosidase inhibitory activity (IC50 = 92.32 ± 1.530-445.20 ± 1.04 µM) against tested standard acarbose (IC50 = 875.75 ± 2.08 µM), except compounds 2 and 4, which appeared as inactive. Among them, compound 9 (IC50 = 92.32 ± 1.530 µM) was the most potent inhibitor of α-glucosidase enzyme. Molecular docking studies revealed that compounds 6, and 9 interacted with the key amino acid residues of α-glucosidase via H-bonding, and π-π stacking interactions. α-Glucosidase is a key target for the anti-diabetic drug development, and its inhibitors are known to exert anti hyperglycemic effect and help in lowering of post-prandial blood glucose levels.

Synthesis, crystal structure and Hirshfeld Surface analysis of benzamide derivatives of thiourea as potent inhibitors of α-glucosidase in-vitro.

Benzamide based structural analogues 1-15 were synthesized, and evaluated for α-glucosidase inhibition activity in vitro for the first time. Compounds 1-9 were found to be known, while compounds 10-15 were found to be new. However, to the best of our knowledge we are reporting α-glucosidase inhibitory activity of these bezamide derivatives of thiourea for the first time. Compounds 1, 3, 6-8, 10-14 were found to be potent inhibitors of α-glucosidase within IC50 range of 20.44-333.41 µM, in comparison to the standard inhibitor, acarbose (IC50 = 875.75 ± 2.08 µM). Mode of the enzyme inhibition was determined on the basis of kinetic studies which demonstrated that compounds 8, and 10 were non-competitive and competitive inhibitors of α-glucosidase enzyme, respectively. These compounds were also evaluated for their DPPH radical scavenging activity, and cytotoxicity against 3T3 mouse fibroblast cell lines. All synthesized compounds showed a significant to moderate DPPH radical scavenging activity and appeared to be non-cytotoxic except compound 9 which showed cytotoxicity against 3T3 normal mouse fibroblast cell lines. A single crystal X-ray and Hirshfeld Surface analysis of a representative compound is also presented.

Anti-Inflammatory Principles from Tamarix aphylla L.: A Bioassay-Guided Fractionation Study.

Natural products have served as primary remedies since ancient times due to their cultural acceptance and outstanding biodiversity. To investigate whether Tamarix aphylla L. modulates an inflammatory process, we carried out bioassay-guided isolation where the extracts and isolated compounds were tested for their modulatory effects on several inflammatory indicators, such as nitric oxide (NO), reactive oxygen species (ROS), proinflammatory cytokine; tumour necrosis factor (TNF-α), as well as the proliferation of the lymphocyte T-cells. The aqueous ethanolic extract of the plant inhibited the intracellular ROS production, NO generation, and T-cell proliferation. The aqueous ethanolic crude extract was partitioned by liquid-liquid fractionation using n-hexane (n-C6H6), dichloromethane (DCM), ethyl acetate (EtOAc), n-butanol (n-BuOH), and water (H2O). The DCM and n-BuOH extracts showed the highest activity against most inflammatory indicators and were further purified to obtain compounds 1-4. The structures of 3,5-dihydroxy-4',7-dimethoxyflavone (1) and 3,5-dihydroxy-4-methoxybenzoic acid methyl ester (2) from the DCM extracts; and kaempferol (3), and 3-hydroxy-4-methoxy-(E)-cinnamic acid (4) from the n-BuOH extract were elucidated by different spectroscopic tools, including MS, NMR, UV, and IR. Compound 2 inhibited the production of ROS and TNF-α, whereas compound 3 showed inhibitory activity against all the tested mediators. A better understanding of the potential aspect of Tamarix aphylla L. derivatives as anti-inflammatory agents could open the door for the development of advanced anti-inflammatory entities.