Farukh Jabeen

Iminothiazoline-Sulfonamide Hybrids as Jack Bean Urease Inhibitors; Synthesis, Kinetic Mechanism and Computational Molecular Modeling

The present work reports the synthesis of several 2‐iminothiazoline derivatives of sulfanilamide (3a–j) as inhibitors of jack bean ureases. The title compounds were synthesized by the heterocyclization of sulfanilamide thioureas with propragyl bromide in dry ethanol in the presence of 1,8‐Diazabicyclo[5.4.0]undec‐7‐ene as a base. All of the compounds showed higher urease inhibitory activity than the standard thiourea. The compounds (3h) and (3i) exhibited excellent enzyme inhibitory activity with IC50 0.064 and 0.058 μm, respectively, while IC50 of thiourea is 20.9 μm. The kinetic mechanism analyzed by Dixon plot showed that compound (3h) is a mixed‐type inhibitor while (3i) is a competitive one. Docking studies suggested that Asp633, Ala636, His492, Ala440, Lue523, Asp494 and Arg439 are the major interacting residues in the binding site of the protein and may have an instrumental role in the inhibition of enzymes function. 2‐iminothiazoline analogues (3a–j) showed good docking score (−10.6466 to −8.7215 Kcal/mol) and binding energy (London dG ranging from −14.4825 to −10.4087 Kcal/mol) which is far better than the standard thiourea (binding score in S field −4.5790 Kcal/mol London dG −4.7726 Kcal/mol). Our results inferred compound (3i) may serve as a structural model for the design of most potent urease inhibitors.

Influence of plasma-activated compounds on melanogenesis and tyrosinase activity

Many organic chemists around the world synthesize medicinal compounds or extract multiple compounds from plants in order to increase the activity and quality of medicines. In this work, we synthesized new eugenol derivatives (ED) and then treated them with an N2 feeding gas atmospheric pressure plasma jet (APPJ) to increase their utility. We studied the tyrosinase-inhibition activity (activity test) and structural changes (circular dichroism) of tyrosinase with ED and plasma activated eugenol derivatives (PAED) in a cell-free environment. Later, we used docking studies to determine the possible interaction sites of ED and PAED compounds with tyrosinase enzyme. Moreover, we studied the possible effect of ED and PAED on melanin synthesis and its mechanism in melanoma (B16F10) cells. Additionally, we investigated the structural changes that occurred in activated ED after plasma treatment using nuclear magnetic resonance (NMR). Hence, this study provides a new perspective on PAED for the field of plasma medicine.

Facile and expedient access to bis-coumarin–iminothiazole hybrids by molecular hybridization approach: synthesis, molecular modelling and assessment of alkaline phosphatase inhibition, anticancer and antileishmanial potential

In the design of new drugs, the hybridization approach might allow obtaining molecules with improved biological activity with respect to the corresponding lead compounds. Thus, adopting this approach, a new series of novel bis-coumarin–iminothiazole hybrids was designed, synthesized and tested for their biological action against alkaline phosphatase, leishmaniasis and cancerous cells. The structures of the synthesized hybrid compounds (5a–m) were characterized and established by using spectro-analytical data. The synthesized analogues were evaluated against alkaline phosphatase where compound 5j was emerged as a potent inhibitor with IC50 value of 1.38 ± 0.42 μM. This inhibitory efficacy is two-fold higher as compared to the standard inhibitor. The synthesized compounds were also assayed for their anti-leishmanial potential against Leishmania major and compound 5i was observed as the lead candidate with 70.4% inhibition. The prepared compounds also showed cytotoxic behavior against kidney fibroblast (BHK-21) and lung carcinoma (H-157) cancer cell lines. Molecular docking of the synthesized library of iminothiazole derivatives against ALP was performed to delineate ligand–protein interactions at molecular level which suggested that the major interacting residues in the binding sites of the proteins might have an instrumental role in the inhibition of enzymes function. Our results inferred that compounds 5j–m may serve as potential surrogates for the development of potent inhibitors of ALP.

Similarity analysis, synthesis, and bioassay of antibacterial cyclic peptidomimetics

Summary The chemical similarity of antibacterial cyclic peptides and peptidomimetics was studied in order to identify new promising cyclic scaffolds. A large descriptor space coupled with cluster analysis was employed to digitize known antibacterial structures and to gauge the potential of new peptidomimetic macrocycles, which were conveniently synthesized by acylbenzotriazole methodology. Some of the synthesized compounds were tested against an array of microorganisms and showed antibacterial activity against Bordetella bronchistepica, Micrococcus luteus, and Salmonella typhimurium.

Dual inhibition of the α-glucosidase and butyrylcholinesterase studied by Molecular Field Topology Analysis

A striking dual inhibition of enzymes α-glucosidase and butyrylcholinesterase by small drug-like molecules, including 1,4-disubstituted-1,2,3-triazoles, chalcones, and benzothiazepines, was rationalized with the help of Molecular Field Topology Analysis, a 3D QSAR technique similar to CoMFA. A common pharmacophore supported the concept of a link existing between type-2 diabetes mellitus and Alzheimers disease. These findings will be instrumental for rational design of drug candidates for both of these conditions.

Unraveling the Alkaline Phosphatase Inhibition, Anticancer, and Antileishmanial Potential of Coumarin-Triazolothiadiazine Hybrids: Design, Synthesis, and Molecular Docking Analysis.

A series of new coumarin–triazolothiadiazine hybrid compounds (5a–j) was designed and synthesized by using the molecular hybridization concept. The cyclocondensation reaction involves the coumarinyl 4‐amino‐1,2,4‐triazole and a range of bromo‐acetophenones, delivering the desired products in good yields. The structures of the synthesized compounds were established on the basis of spectro‐analytical data. The prepared compounds were evaluated against alkaline phosphatase (ALP) where compound 5j incorporating bis‐coumarinyl motifs at the 3‐ and 6‐positions of the heteroaromatic core turned out to be a potent inhibitor with an IC50 value of 1.15 ± 1.0 µM. The synthesized compounds were also tested against Leishmania major and 5h was the lead member with an IC50 value of 0.89 ± 0.08 μM. Anticancer activity was also determined using kidney fibroblast (BHK‐21) and lung carcinoma (H‐157) cancer cell lines. Compound 5i showed highest cytotoxic potential against H‐157 cells with an IC50 value of 1.01 ± 0.12 μM, which is an improved inhibition compared to the standards (vincristine and cisplatin) used in this assay. Molecular docking studies were carried out on the synthesized library of coumarin–triazolothiadiazine hybrids against ALP. Almost all of the compounds showed strong interactions with the key residues of the active site of the receptor. In case of compounds 5a–c, 5h, and 5j, docking results positively complemented the experimental screening. These results provided substantial evidence for the further development of these compounds as potent inhibitors of ALP.

Synthesis, molecular docking and anticancer studies of peptides and iso-peptides

Chiral peptides and iso-peptides were synthesized in excellent yield by using benzotriazole mediated solution phase synthesis. Benzotriazole acted both as activating and leaving group, eliminating frequent use of protection and subsequent deprotection. The procedure was based on the hypothesis that epimerization should be suppressed in solution due to a faster coupling rate than SPPS. All the synthesized peptides complied with Lipinskis Ro5 except for the rotatable bonds. Inhibition of cell proliferation of cancer cell lines is one of the most commonly used methods to study the effectiveness of any anticancer agents. Synthesized peptides and iso-peptides were tested against three cancer cell lines (MCF-7, MDA-MB 231) to determine their anti-proliferative potential. NFkB was also determined. Molecular docking studies were also carried out to complement the experimental results.

Synthesis, characterization of novel chitosan based water dispersible polyurethanes and their potential deployment as antibacterial textile finish

Our current research work comprised of synthesis of a series of novel chitosan based water dispersible polyurethanes. The synthesis was carried out in three steps, in first step, the NCO end capped PU-prepolymer was formed through the reaction between Polyethylene glycol (PEG) (Mn = 600), Dimethylolpropionic acid (DMPA) and Isophorone diisocyanate (IPDI). In second step, the neutralization step was carried out by using Triethylamine (TEA) which resulted the formation of neutralized NCO terminated PU-prepolymer, after that the last step chain extension was performed by the addition of chitosan and followed the formation of dispersion by adding calculated amount of water. The proposed structure of CS-WDPUs was confirmed by using FTIR technique. The antimicrobial activities of the plain weave poly-cotton printed and dyed textile swatches after application of CS-WDPUs were also evaluated. The results showed that the chitosan incorporation in to PU backbone has markedly enhanced the antibacterial activity of WDPUs. These synthesized CS-WDPUs are eco-friendly antimicrobial finishes (using natural bioactive agents such as chitosan) with potential applications on polyester/cotton textiles.

Synthesis, Antibacterial and Antileishmanial Activity, Cytotoxicity, and Molecular Docking of New Heteroleptic Copper(I) Complexes with Thiourea Ligands and Triphenylphosphine

A series of copper(I) complexes with triphenylphosphine and N-acyl-N′-arylthioureas were synthesized and characterized by elemental analysis and IR and NMR (1H, 13C, 31P) spectroscopy. The thiourea ligands and their copper(I) triphenylphosphine complexes were screened for antibacterial and antileishmanial activities and cytotoxicity. The synthesized compounds showed much better activity as compared to glucantime and Kanamycin used as reference drugs. The thiourea ligands showed better activity than their Cu(I) complexes. The molecular docking technique was utilized to ascertain the mechanism of action toward molecular targets (GP63 and 16S-rRNA A-site). It was found that the ligands and complexes were stabilized at the active site by electrostatic and hydrophobic forces, consistent with the corresponding experimental results. The in silico study of the binding pattern predicted that one of the synthesized ligands, N-(5-chloro-2-nitrophenyl)-N′- pentanoylthiourea, can serve as a potential surrogate for hit-to-lead generation and design of novel antibacterial and antileishmanial agents.

Synthesis, single crystal analysis, biological and docking evaluation of tetrazole derivatives

Tetrazoles are conjugated nitrogen-rich heterocycles considered as bio-isosteres of carboxylic acids. Tetrazoles owing to their conjugated structures serve as biologically relevant potent scaffolds. The present research paper reports the successful synthesis and single crystal analysis of three different tetrazole derivatives (2, 4, 6). The synthesized tetrazole derivatives were evaluated for their possible cytotoxicity LD50 (52.89, 49.33, 17.28 μg/ml) and antileishmanial activities IC50 (0.166, 10, 5.0 μg/ml). Moreover, molecular docking studies were performed to determine the possible interaction sites of the tetrazole derivatives (2, 4, 6) with TryR, an enzyme involved in the redox metabolism of the Leishmania parasite. Docking computations demonstrates that the tetrazole derivatives (2, 4, 6) established prominent binding interactions with the key residues of the TryR and possess the potential to effectively inhibit the catalytic activities of the enzyme. The results suggested that the synthesized tetrazole derivative (2, 4, 6) can be possible hit candidates which can be tested further against amastigote stage of parasite and then in an animal model of leishmaniasis.