Aliya Ibrar

Transition-metal-free synthesis of oxazoles: valuable structural fragments in drug discovery

Oxazole, a central structural motif of numerous complex natural products and pharmaceuticals, is closely associated with the development of contemporary drug discovery research due to a diverse portfolio of biological functions. The remarkable medicinal potential and ubiquitous prevalence of oxazoles in synthetic drugs have provided an impetus for their easy accessibility and much effort has been exerted to develop new and efficient methods. In this regard, metal-free reactions for the synthesis of oxazole heterocycles have emerged as an eminent concept over the years due to the toxicity, price or scarcity of some transition-metal-catalyzed reactions. In this review, the various concepts that have proved useful for the development of robust and transition-metal-free methodologies for the construction of oxazole skeleton are presented. A brief description of mechanistic investigations and synthetic utility of these motifs have also been discussed.

Coumarin-thiazole and -oxadiazole derivatives: Synthesis, bioactivity and docking studies for aldose/aldehyde reductase inhibitors

In continuation of our previous efforts directed towards the development of potent and selective inhibitors of aldose reductase (ALR2), and to control the diabetes mellitus (DM), a chronic metabolic disease, we synthesized novel coumarin-thiazole 6(a-o) and coumarin-oxadiazole 11(a-h) hybrids and screened for their inhibitory activity against aldose reductase (ALR2), for the selectivity against aldehyde reductase (ALR1). Compounds were also screened against ALR1. Among the newly designed compounds, 6c, 11d, and 11g were selective inhibitors of ALR2. Whereas, (E)-3-(2-(2-(2-bromobenzylidene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one 6c yielded the lowest IC50 value of 0.16±0.06μM for ALR2. Moreover, compounds (E)-3-(2-(2-benzylidenehydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6a; IC50=2.94±1.23μM for ARL1 and 0.12±0.05μM for ARL2) and (E)-3-(2-(2-(1-(4-bromophenyl)ethylidene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6e; IC50=1.71±0.01μM for ARL1 and 0.11±0.001μM for ARL2) were confirmed as dual inhibitors. Furthermore, compounds 6i, 6k, 6m, and 11b were found to be selective inhibitors for ALR1, among which (E)-3-(2-(2-((2-amino-4-chlorophenyl)(phenyl)methylene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6m) was most potent (IC50=0.459±0.001μM). Docking studies performed using X-ray structures of ALR1 and ALR2 with the given synthesized inhibitors showed that coumarinyl thiazole series lacks the carboxylate function that could interact with the anionic binding site being a common ALR1/ALR2 inhibitors trait. Molecular docking study with dual inhibitor 6e also suggested plausible binding modes for the ALR1 and ALR2 enzymes. Hence, the results of this study revealed that coumarinyl thiazole and oxadiazole derivatives could act as potential ALR1/ALR2 inhibitors.

Symmetrical aryl linked bis-iminothiazolidinones as new chemical entities for the inhibition of monoamine oxidases: Synthesis, in vitro biological evaluation and molecular modelling analysis

The multifactorial nature of Parkinsons disease necessitates the development of new chemical entities with inherent ability to address key pathogenic processes. To this end, two series of new symmetrical 1,2- and 1,4-bis(2-aroyl/alkoylimino-5-(2-methoxy-2-oxoethylidene)-4-oxo-thiazolidin-3-yl)benzene derivatives (3a-g and 5a-e) were synthesized in good yields by the cyclization of 1,2- and 1,4-bis(N-substituted thioureido)benzene intermediates with dimethyl acetylenedicarboxylate (DMAD) in methanol at ambient temperature. The bis-iminothiazolidinone compounds were investigated in vitro for their inhibition of monoamine oxidase (MAO-A & MAO-B) enzymes with the aim to identify new and distinct pharmacophores for the treatment of neurodegenerative disorders like Parkinsons disease. Most of the designed compounds exhibited good inhibitory efficacy against monoamine oxidases. Compound 5a was identified as the most potent inhibitor of MAO-A depicting an IC50 value of 0.001μM, a 4-fold stronger inhibitory strength compared to standard inhibitor (clorgyline: IC50=0.0045μM). Molecular docking studies provided insights into enzyme-inhibitor interactions and a rationale for the observed inhibition towards monoamine oxidases.

Pharmacological Evaluation and Docking Studies of 3-Thiadiazolyl- and Thioxo-1,2,4-triazolylcoumarin Derivatives as Cholinesterase Inhibitors

Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is considered a promising strategy for the treatment of Alzheimers disease (AD). This research project aims to provide a comprehensive knowledge of newly synthesized coumarin analogues with anti-AD potential. In the present work a series of 3-thiadiazolyl- and thioxo-1,2,4-triazolylcoumarins derivatives were designed, synthesized, and tested as potent inhibitors of cholinesterases. These compounds were assayed against AChE from electrophorus electricus and rabbit; and BChE from horse serum and rabbit by Ellmans method using neostigmine methylsulphate and donepezil as reference drugs. Some of the assayed compounds proved to be potent inhibitors of AChE and BChE with Ki values in the micromolar range. 4b was found to be the most active compound with Ki value 0.028 ± 0.002u2009μM and higher selectivity for AChE/BChE. The ability of 4b to interact with AChE was further confirmed through computational studies, in which a primary binding was proved to occur at the active gorge site, and a secondary binding was revealed at the peripheral anionic site. Structure activity relationships of prepared compounds were also discussed.

Complex electronic interplay of σ-hole and π-hole interactions in crystals of halogen substituted 1,3,4-oxadiazol-2(3H)-thiones

In this study, we have performed a detailed analysis of the nature and strength of different intermolecular interactions present in the crystal structures of four biologically active derivatives of 1,3,4-oxadiazol-2(3H)-thiones. The study was primarily focused on obtaining detailed physical insights into the differential nature of the σ-hole and π-hole interactions that exist in the solid state in this class of compounds. It is found that the directionality of an interaction plays a very important role in categorizing these interactions as being σ-hole and π-hole in origin. The presence of a σ-hole (on the S, Cl and Br atoms) and π-holes (in the oxadiazole and benzyl rings) is clearly evident from the molecular electrostatic potential maps. The presence of these ubiquitous interactions was further confirmed via QTAIM analysis by the presence of (3, −1) bond critical points (bcps) between the interacting atoms with acceptable topological parameters (ρbcp; ∇2ρbcp). Furthermore, Hirshfeld 2D fingerprint plots helped in quantitatively determining the role of different interactions in the crystal packing of the four reported structures.

Exploration of aroyl/heteroaroyl iminothiazolines featuring 2,4,5-trichlorophenyl moiety as a new class of potent, selective, and in vitro efficacious glucosidase inhibitors

A series of iminothiazolines (4a-j) featuring 2,4,5-trichlorophenyl moiety and aroyl/heteroaroyl substituents has been prepared from readily accessible thioureas. In-vitro screening against glucosidase enzymes showed highly specific inhibition of α-glucosidase with a marked dependence of the potency upon the nature of the aroyl/heteroaroyl substituents. The most potent representatives, bearing ortho-tolyl and bulky naphthyl groups displayed the highest inhibitory potential with IC50 value of 0.15±0.01µM compared to standard drug acarbose (IC50=38.2±0.12µM). Several other derivatives (4c, 4d, 4i and 4j) were also significantly powerful and selective inhibitors of α-glucosidase. Binding interactions of potent compounds 4b, 4c, 4h and 4i with α-glucosidase were explored by molecular docking simulation. These results clearly identified a new class of structural leads which can be further investigated for the development of promising α-glucosidase inhibitors for the prevention of diabetes mellitus.

Quinolinic carboxylic acid derivatives as potential multi-target compounds for neurodegeneration: monoamine oxidase and cholinesterase inhibition

BACKGROUNDnParkinsons disease (PD), a debilitating and progressive disorder, is among the most challenging and devastating neurodegenerative diseases predominantly affecting the people over 60 years of age.nnnOBJECTIVESnTo confront PD, an advanced and operational strategy is to design single chemical functionality able to control more than one target instantaneously.nnnMETHODSnIn this endeavor, for the exploration of new and efficient inhibitors of Parkinsons disease, we synthesized a series of quinoline carboxylic acids (3a-j) and evaluated their in vitro monoamine oxidase and cholinesterase inhibitory activities. The molecular docking and in silico studies of the most potent inhibitors were performed to identify the probable binding modes in the active site of the monoamine oxidase enzymes. Moreover, molecular properties were calculated to evaluate the druglikeness of the compounds.nnnRESULTSnThe biological evaluation results revealed that the tested compounds were highly potent against monoamine oxidase (A & B), 3c targeted both the isoforms of MAO with IC50 values of 0.51 ± 0.12 and 0.51 ± 0.03 µM, respectively. The tested compounds also demonstrated high and completely selective inhibitory action against acetylcholinesterase (AChE) with IC50 values ranging from 4.36 to 89.24 µM. Among the examined derivatives, 3i was recognized as the most potent inhibitor of AChE with an IC50 value of 4.36 ± 0.12 ±µM.nnnCONCLUSIONnThe compounds appear to be promising inhibitors and could be used for the future development of drugs targeting neurodegenerative disorders.