Zahid Shafiq

Light-triggered in vivo activation of adhesive peptides regulates cell adhesion, inflammation and vascularization of biomaterials

Materials engineered to elicit targeted cellular responses in regenerative medicine must display bioligands with precise spatial and temporal control. Although materials with temporally regulated presentation of bioadhesive ligands using external triggers, such as light and electric fields, have been recently realized for cells in culture, the impact of in vivo temporal ligand presentation on cell-material responses is unknown. Here, we present a general strategy to temporally and spatially control the in vivo presentation of bioligands using cell adhesive peptides with a protecting group that can be easily removed via transdermal light exposure to render the peptide fully active. We demonstrate that non-invasive, transdermal time-regulated activation of cell-adhesive RGD peptide on implanted biomaterials regulates in vivo cell adhesion, inflammation, fibrous encapsulation, and vascularization of the material. This work shows that triggered in vivo presentation of bioligands can be harnessed to direct tissue reparative responses associated with implanted biomaterials.

In vitro antibacterial, antifungal & cytotoxic activity of some isonicotinoylhydrazide Schiff's bases and their cobalt (II), copper (II), nickel (II) and zinc (II) complexes

Isonicotinoylhydrazide Schiffs bases formed by the reaction of substituted and unsubstituted furyl-2-carboxaldehyde and thiophene-2-carboxaldehyde with isoniazid and, their Co (II), Cu (II), Ni (II) and Zn (II) complexes have been synthesized, characterized and screened for their in vitro antibacterial activity against Mycobacterium tuberculosis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella typhi, Shigella dysenteriae, Bacillus cereus, Corynebacterium diphtheriae, Staphylococcus aureus and Streptococcus pyogenes bacterial strains and for in vitro antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glabrata. The results of these studies show the metal complexes to be more antibacterial and antifungal against one or more bacterial/fungal strains as compared to the uncomplexed compounds. The brine shrimp bioassay indicated Schiffs bases, L3 and L6 and, their Cu (II) and Ni (II) metal complexes to be cytotoxic against Artemia salina, while all other compounds were inactive (LD50>1000).

Antibacterial Strategies from the Sea: Polymer-Bound Cl-Catechols for Prevention of Biofilm Formation

Inspired by the amino acid 2-chloro-4,5-dihydroxyphenylalanine (Cl-DOPA), present in the composition of the proteinaceous glue of the sandcastle worm Phragmatopoma californica, a simple strategy is presented to confer antifouling properties to polymer surfaces using (but not releasing) a bioinspired biocide. Cl-Dopamine is used to functionalize polymer materials and hydrogel films easily, to prevent biofilm formation on them.

Synthesis, biological evaluation and molecular docking of N-phenyl thiosemicarbazones as urease inhibitors.

Urease is an important enzyme which breaks urea into ammonia and carbon dioxide during metabolic processes. However, an elevated activity of urease causes various complications of clinical importance. The inhibition of urease activity with small molecules as inhibitors is an effective strategy for therapeutic intervention. Herein, we have synthesized a series of 19 benzofurane linked N-phenyl semithiocarbazones (3a-3s). All the compounds were screened for enzyme inhibitor activity against Jack bean urease. The synthesized N-phenyl thiosemicarbazones had varying activity levels with IC50 values between 0.077 ± 0.001 and 24.04 ± 0.14 μM compared to standard inhibitor, thiourea (IC50 = 21 ± 0.11 μM). The activities of these compounds may be due to their close resemblance of thiourea. A docking study with Jack bean urease (PDB ID: 4H9M) revealed possible binding modes of N-phenyl thiosemicarbazones.

Robustness of thioamide dimer synthon, carbon bonding and thioamide–thioamide stacking in ferrocene-based thiosemicarbazones

The role of thioureas in crystal engineering as robust supramolecular synthons is now recognized, but their analogs, namely thiosemicarbazones/N-iminothioureas, have not received the attention they deserve. A series of five structurally related ferrocene-based thiosemicarbazones 1–5 have been designed, synthesized and crystallographically characterized in order to investigate the prevalence of the thioamide dimer synthon and carbon bonding. All of the compounds have shown a general preference for the adoption of the cis, trans conformation about the central thiourea moiety which is ideal for the formation of a dimeric hydrogen-bonded R22(8) {⋯H–N–CS}2 synthon as the building block. Therefore, this dimeric synthon is observed in all of the compounds, with the methyl group particularly set for playing its supportive stabilization role through C–H⋯S and carbon bonding interactions. Carbon bonding has been observed in all of the compounds except compound 2. The centrosymmetrically arranged thioamide protons present in trans conformation through N–H⋯H–C interactions give rise to the formation of tapes of varying topology in all of the compounds except 3, where a staircase arrangement of dimeric molecules is observed. Another notable feature of the crystal packing of 1–5 is the presence of thioamide–thioamide stacking, which has been observed in all five compounds. The prevalence of the thioamide dimer synthon, carbon bonding, and observation of new thioamide–thioamide stacking interactions indicate a much larger role for this class of compounds as a design element in crystal engineering than anticipated so far.

Gauging and Tuning Cross-Linking Kinetics of Catechol-PEG Adhesives via Catecholamine Functionalization

The curing time of an adhesive material is determined by the polymerization and cross-linking kinetics of the adhesive formulation and needs to be optimized for the particular application. Here, we explore the possibility of tuning the polymerization kinetics and final mechanical properties of tissue-adhesive PEG gels formed by polymerization of end-functionalized star-PEGs with catecholamines with varying substituents. We show strong differences in cross-linking time and cohesiveness of the final gels among the catecholamine-PEG variants. Installation of an electron-withdrawing but π-electron donating chloro substituent on the catechol ring resulted in faster and more efficient cross-linking, while opposite effects were observed with the strongly electron-withdrawing nitro group. Chain substitution slowed down the kinetics and hindered cross-linking due either to chain breakdown (β-OH group, in norepinephrine) or intramolecular cyclization (α-carboxyl group, in DOPA). Interesting perspectives derive from use of mixtures of catecholamine-PEG precursors offering further opportunities for fine-tuning of the curing parameters. These are interesting properties for the application of catecholamine-PEG gels as tissue glues or biomaterials for cell encapsulation.

Coumarin-based thiosemicarbazones as potent urease inhibitors: synthesis, solid state self-assembly and molecular docking

A series of coumarin-based thiosemicarbazones and their metal complexes have been synthesized and their in vitro potency against urease was evaluated. Single crystal X-ray crystallographic studies were carried out for compound 14 to investigate the solid state self-assembly which showed a preference for the S-conformation owing to intramolecular hydrogen bonding. An in vitro urease inhibition assay revealed coumarin-thiosemicarbazone 12 as the most potent inhibitor (IC50 value of 2.23 ± 0.14 μM) compared to thiourea, used as standard (IC50 value of 21.25 ± 0.15 μM). Similarly, compounds 4, 6, 7, 9, 15 & 16 showed excellent urease inhibition activity with IC50 values ranging from 4.15 ± 0.17 to 16.95 ± 0.12 μM. Furthermore, compounds 3, 8, 11 & 13 also showed good activities (IC50 values ranging from 33.86 ± 0.12 to 43.12 ± 0.19 μM) against this enzyme. However, the metal complexes of these compounds showed low activity against urease. Molecular docking with the most cogent ligand against urease was also performed to assess the putative binding mode of the synthesized compounds. Potent compound 12 can serve as a potential lead for further chemical tuning towards drug candidate development.

Robustness of a thioamide {⋯H–N–CS}2 synthon: synthesis and the effect of substituents on the formation of layered to cage-like supramolecular networks in coumarin–thiosemicarbazone hybrids

The applications of thioureas in crystal engineering have increased dramatically over the past few years. However, their analogs namely N-imino thioureas/thiosemicarbazones are largely ignored, despite the fact that these can be more interesting with respect to crystal engineering applications due to the presence of an additional N-imino moiety. Aiming to highlight their importance in crystal engineering/supramolecular chemistry, three structurally related coumarin–thiosemicarbazone hybrids (3a–3c) have been designed, synthesized and crystallographically characterized. All of the compounds showed a general preference for the adoption of the cis, trans conformation around the central thiourea moiety; a conformation which is ideal for the formation of a dimeric hydrogen-bonded R22(8){⋯H–N–CS}2 synthon as the building block. Therefore, this dimeric synthon is observed in all of the compounds, regardless of the formation of layered to cage-like three dimensional supramolecular networks depending on different substituents. The prevalence of the cis, trans conformation and the robustness of the thioamide dimer synthon in thiosemicarbazones indicate its potential use as a design element in crystal engineering.

N'-[(E)-4-Hydr-oxy-3-methoxy-benzyl-idene]benzohydrazide.

In the title compound, C15H14N2O3, the phenyl ring is disordered over two set of sites with an occupancy ratio of 0.810 (3):0.190 (3); the dihedral angle between the two components is 72.3 (4)°. The benzene and phenyl rings are oriented at dihedral angles of 69.18 (8) and 26.0 (5)° (major and minor orientations, respectively), and an intramolecular O—H⋯O hydrogen bond occurs. In the crystal, molecules are linked by N—H⋯O, O—H⋯O and C—H⋯O interactions, generating a three-dimensional network.

Me3N-promoted synthesis of 2,3,4,4a-tetrahydroxanthen-1-one: preparation of thiosemicarbazone derivatives, their solid state self-assembly and antimicrobial properties

A new strategy has been used to synthesize 2,3,4,4a-tetrahydroxanthen-1-one (3) in high yield. Using the Me3N-promoted domino Baylis–Hillman/oxa-Michael reaction sequence at room temperature, the reaction of salicyldehyde (1) with cyclohexanone (2) provided 3 in 88% yield, which further undergo reaction with thiosemicarbazides (4) to afford a series of new xanthene-based thiosemicarbazones (5a–5j). All the synthesized compounds were characterized by their physical and spectral data. The solid state self-assembly studies for 5d and 5i were carried out by the single crystal X-ray technique to investigate the prevalence of the thioamide dimer synthon and its role in molecular alignment in the solid state. Furthermore, the compounds (5a–5j) were tested for their antibacterial activity. The compounds 5b, 5c, 5d and 5i showed excellent antibacterial activity against one or more of the tested bacterial strains. Notably, the antibacterial activity for the compound 5c was found comparable to the standard reference drug, ciprofloxacin against Salmonella typhi.