Pervaiz Ali Channar

Isonicotinohydrazones as Inhibitors of Alkaline Phosphatase and Ecto-5'-nucleotidase.

A series of isonicotinohydrazide derivatives was synthesized and tested against recombinant human and rat ecto‐5′‐nucleotidases (h‐e5′NT and r‐e5′NT) and alkaline phosphatase isozymes including both bovine tissue‐non‐specific alkaline phosphatase (b‐TNAP) and tissue‐specific calf intestinal alkaline phosphatase (c‐IAP). These enzymes are implicated in vascular calcifications, hypophosphatasia, solid tumors, and cancers, such as colon, lung, breast, pancreas, and ovary. All tested compounds were active against both enzymes. The most potent inhibitor of h‐e5′NT was derivative (E)‐N′‐(1‐(3‐(4‐fluorophenyl)‐5‐phenyl‐4,5‐dihydro‐1H‐pyrazol‐1‐yl)ethylidene)isonicotinohydrazide (3j), whereas derivative (E)‐N′‐(4‐hydroxy‐3‐methoxybenzylidene)isonicotinohydrazide (3g) exhibited significant inhibitory activity against r‐e5′NT. In addition, the derivative (E)‐N′‐(4′‐chlorobenzylidene)isonicotinohydrazide (3a) was most potent inhibitor against calf intestinal alkaline phosphatase and the derivative (E)‐N′‐(4‐hydroxy‐3‐methoxybenzylidene)isonicotinohydrazide (3g) was found to be most potent inhibitor of bovine tissue‐non‐specific alkaline phosphatase. Furthermore, putative binding modes of potent compounds against e5′NT (human and rat e5′NT) and AP (including b‐TNAP and c‐IAP) were determined computationally.

2-(Hetero(aryl)methylene)hydrazine-1-carbothioamides as Potent Urease Inhibitors

A small series of 2‐(hetero(aryl)methylene) hydrazine‐1‐carbothioamides including two aryl derivatives was synthesized and tested for their inhibitory activity against urease. Compound (E)‐2‐(Furan‐2‐ylmethylene) hydrazine‐1‐carbothioamide (3f), having a furan ring, was the most potent inhibitor of urease with an IC50 value of 0.58 μm. Molecular modeling was carried out through docking the designed compounds into the urease binding site to predict whether these derivatives have analogous binding mode to the urease inhibitors. The study revealed that all of the tested compounds bind with both metal atoms at the active site of the enzyme. The aromatic ring of the compounds forms ionic interactions with the residues, Ala(440), Asp(494), Ala(636), and Met(637).

Hybrid Pharmacophoric Approach in the Design and Synthesis of Coumarin Linked Pyrazolinyl as Urease Inhibitors, Kinetic Mechanism and Molecular Docking

The current research article reports the synthesis of coumarinyl pyrazolinyl thioamide derivatives and their biological activity as inhibitors of jack bean urease. The coumarinyl pyrazolinyl thioamides were synthesized by reacting thiosemicarbazide with newly synthesized chalcones to afford the products in good yields and the synthesized compounds were purified by recrystallization. Coumarinyl pyrazolinyl thioamide derivatives 5a – 5q showed significant activity against Urease enzyme and also exhibited good antioxidant potential. The compound 3‐(2‐oxo‐2H‐chromen‐3‐yl)‐5‐phenyl‐4,5‐dihydro‐1H‐pyrazole‐1‐carbothioamide (5n) was found to be superior agent in the series with an IC50 = 0.358 ± 0.017 μm compared to standard thiourea with an IC50 = 4720 ± 174 μm. To undermine the binding mode of inhibition kinetic studies were performed for most potent derivative and it was found that compound 5n inhibits urease enzyme by non‐competitive mode of inhibition. Molecular docking studies were carried out to delineate the binding affinity of the synthesized derivatives.

Synthesis, enzyme inhibitory kinetics, and computational studies of novel 1-(2-(4-isobutylphenyl) propanoyl)-3-arylthioureas as Jack bean urease inhibitors

In this article, synthesis of a novel 1‐(2‐(4‐isobutylphenyl)propanoyl)‐3‐arylthioureas (4a–j) as jack bean urease inhibitors has been described. Freshly prepared 2‐(4‐isobutylphenyl) propanoyl isothiocyanate was treated with substituted aromatic anilines in one pot using anhydrous acetone. The compounds 4e, 4h, and 4j showed IC50 values 0.0086 nm, 0.0081 nm, and 0.0094 nm, respectively. The enzyme inhibitory kinetics results showed that compound 4h inhibit the enzyme competitively while derivatives 4e and 4j are the mixed type inhibitors. The compound 4h reversibly binds the urease enzyme showing Ki value 0.0012 nm. The Ki values for 4e and 4j are 0.0025 nm and 0.003 nm, respectively. The antioxidant activity results reflected that compounds 4b, 4i, and 4j showed excellent radical scavenging activity. Moreover, the cytotoxic activity of the target compounds was evaluated using brine shrimp assay and it was found that all of the synthesized compounds exhibited no cytotoxic effects to brine shrimps. The computational molecular docking and molecular dynamic simulation of title compounds were also performed, and results showed that the wet laboratory findings are in good agreement to the dry laboratory results. Based upon our results, it is proposed that compound 4h may act as a lead candidate to design the clinically useful urease inhibitors.

Sulfonamide-Linked Ciprofloxacin, Sulfadiazine and Amantadine Derivatives as a Novel Class of Inhibitors of Jack Bean Urease; Synthesis, Kinetic Mechanism and Molecular Docking

Sulfonamide derivatives serve as an important building blocks in the drug design discovery and development (4D) process. Ciprofloxacin-, sulfadiazine- and amantadine-based sulfonamides were synthesized as potent inhibitors of jack bean urease and free radical scavengers. Molecular diversity was explored and electronic factors were also examined. All 24 synthesized compounds exhibited excellent potential against urease enzyme. Compound 3e (IC50 = 0.081 ± 0.003 µM), 6a (IC50 = 0.0022 ± 0.0002 µM), 9e (IC50 = 0.0250 ± 0.0007 µM) and 12d (IC50 = 0.0266 ± 0.0021 µM) were found to be the lead compounds compared to standard (thiourea, IC50 = 17.814 ± 0.096 µM). Molecular docking studies were performed to delineate the binding affinity of the molecules and a kinetic mechanism of enzyme inhibition was propounded. Compounds 3e, 6a and 12d exhibited a mixed type of inhibition, while derivative 9e revealed a non-competitive mode of inhibition. Compounds 12a, 12b, 12d, 12e and 12f showed excellent radical scavenging potency in comparison to the reference drug vitamin C.

Synthesis, computational studies and biological evaluation of new 1-acetyl-3-aryl thiourea derivatives as potent cholinesterase inhibitors

A new series of 1-acetyl-3-aryl thioureas (3f1–15) was synthesized by the reaction of acetyl isothiocyanate with a variety of suitably substituted aromatic anilines. The acetyl isothiocyanate was freshly prepared by reaction of corresonding acid chloride with potassium thiocyanate. The structural confirmation of all compounds was carried out by spectroscopic techniques and in case of 3a by X-ray diffraction study. The newly prepared compounds were subjected to computational studies and evaluated for their cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibition studies. Except 3f9 and 3f15, all the derivatives were found as selective inhibitor of acetylcholinesterase. Compound 3f2 (IC50 ± SEM = 1.99 ± 0.11 µM) was found to be the most potent inhibitor of acetylcholinesterase exhibited ≈11 times greater inhibitory potential than reference inhibitor i.e. neostigmine (IC50 ± SEM = 22.2 ± 3.2 µM). Compound 3f9 was found to be most potent butyrylcholinesterase inhibitor (IC50 ± SEM = 1.33 ± 0.11 µM), exhibiting ≈four times greater selectivity for butyrylcholinesterase over acetylcholinesterase. Molecular docking studies were carried out to determine the binding site interactions of these potent inhibitors with cholinesterases and also supported the experimental observations.

Enzyme inhibitory activities an insight into the structure–Activity relationship of biscoumarin derivatives

Biscoumarin derivatives, a dimeric form of coumarin, are well known derivatives of coumarin, occurred in the bioactive metabolites of marine and terrestrial organisms. On account of pharmacological and biological applications, biscoumarins have long been the subject of innumerable enzyme inhibition studies. In this review the pros and cons of enzyme inhibition studies of biscoumarins as urease inhibitors, aromatase inhibitors, NPPs, α-glucosidase inhibitors, α-amylase inhibitors, HIV-1 integrase inhibition, steroid sulfatase inhibitors and c-Met inhibitors are discussed in a systematic way. Moreover, the review discusses the structure activity relationship of biscoumarin scaffold with enzyme inhibitory potency which would unleash new avenues for further development. The purpose of the current review is to disclose the value of biscoumarins as potent and efficient enzyme inhibitor. This review provides a guideline to elaborate the diversity of biscoumarin inhibitors by exploring the effects of electronic groups linked with biscoumarin nucleus.

Jack Bean Urease Inhibitors, and Antioxidant Activity Based on Palmitic acid Derived 1-acyl-3- Arylthioureas: Synthesis, Kinetic Mechanism and Molecular Docking Studies

A series of acylthioureas was synthesized and their inhibitory effects on the DPPH and jack bean urease were evaluated. The results showed that all of the synthesized compounds exhibited significant jack bean urease inhibitory activities. Especially, 1-(4-chlorophenyl)-3 palmitoylthiourea 5a bearing 4-chloro substituted phenyl ring exhibited the most potent tyrosinase inhibitory activity with an IC50 value 0.0170 μM compared to the IC50 value of 4.720 μM of thiourea used as standard. The inhibition mechanism analyzed by Lineweaver-Burk plots revealed that the type of inhibition of compound 5a on tyrosinase was noncompetitive. The docking study against jack bean urease enzyme was also performed to determine the binding affinity of the compounds. The compounds 4c and 4e showed the highest binding affinity with the active binding site of tyrosinase. The initial structure activity relationships (SARs) analysis suggested that further development of such compounds might be of interest. The statistics of our results endorses that all compounds and particularly 5a may serve as a structural template for the design and development of novel urease inhibitors Graphical Abstract.

Recent synthetic approaches to fipronil, a super-effective and safe pesticide

Fipronil is a heavily substituted pyrazole-based heterocycle, a well-known and extremely effective parasiticide used for both agricultural and non-agricultural purposes. Because of its broad bioactive spectrum, it is effective for animals as well as plants. These exciting features have prompted researchers to develop high-yielding and effective protocols for its synthesis. This review covers the recent synthetic approaches for fipronil and its derivatives.Graphical Abstract

An expedient synthesis of N -(1-(5-mercapto-4-((substituted benzylidene)amino)-4H -1,2,4-triazol-3-yl)-2-phenylethyl)benzamides as jack bean urease inhibitors and free radical scavengers: Kinetic mechanism and molecular docking studies

In this study, some new azomethine‐triazole hybrids 5a–5l derived from N‐benzoyl‐L‐phenylalanine were synthesized and characterized. The synthesized compounds showed first‐rate, urease inhibition, and compounds 5c and 5e were found to be most effective inhibitors with 0.0137 ± 0.00082 μm and 0.0183 ± 0.00068 μm, respectively (thiourea 15.151 ± 1.27 μm). The kinetic mechanism of urease inhibition revealed the compounds 5c and 5e to be non‐competitive inhibitors, whereas compounds 5d and 5j were found to be of mixed‐type inhibitors. Docking studies also indicated better interaction patterns with urease enzyme. The results of enzyme inhibition, kinetic mechanism and molecular docking suggest that these compounds can serve as lead compounds in the design of more effective urease inhibitors.