Sumera Zaib

Quinazolines and quinazolinones as ubiquitous structural fragments in medicinal chemistry: An update on the development of synthetic methods and pharmacological diversification

Nitrogen-rich heterocycles, particularly quinazolines and quinazolinones, represent a unique class of diversified frameworks displaying a broad spectrum of biological functions. Over the past several years, intensive medicinal chemistry efforts have generated numerous structurally functionalized quinazoline and quinazolinone derivatives. Interest in expanding the biological effects, demonstrated by these motifs, is growing exponentially, as indicated by the large number of publications reporting the easy accessibility of these skeletons in addition to the diverse nature of synthetic as well as biological applications. Therefore, the main focus of the present review is to provide an ample but condensed overview on various synthetic approaches providing access to quinazoline and quinazolinone compounds with multifaceted biological activities. Furthermore, mechanistic insights, synthetic utilization, structure-activity relationships and molecular modeling inputs for the potent derivatives have also been discussed.

Organotin(IV) carboxylate derivatives as a new addition to anticancer and antileishmanial agents: design, physicochemical characterization and interaction with Salmon sperm DNA

This article demonstrates the synthesis and characterization of novel organotin(IV) carboxylate complexes and their medicinal applications. Metal complexes and organometallic compounds have growing importance in medicine, particularly in oncology. Organotin derivatives have caught much attention during the last two decades for their potential biocidal activities. In recent years several organotin compounds have been synthesized, some with interesting cytotoxic properties. Here we will focus on the relevance of organotin derivatives as very promising potential candidates in anticancer therapy. Ten new organotin(IV) complexes were synthesized and characterized by using FT-IR, NMR (1H, 13C and 119Sn), elemental analysis, mass spectrometry and single crystal X-ray techniques. The results of infrared spectroscopy of the sodium salt and complexes showed that the coordination took place through the oxygen atoms of the carboxylate group. Crystallographic data for complexes 1 and 3 showed that the tin has a distorted trigonal bipyramidal geometry with the three alkyl groups in the trigonal plane and the two oxygen atoms in the equatorial plane. In the case of complex 4 the geometry is tetrahedral due to the steric hindrance of the bulky phenyl groups. The compounds were screened for in vitro antiproliferative activity against lung carcinoma (H-157) and kidney fibroblast (BHK-21) cell lines and revealed significant anticancer activity. They were also tested for antileishmanial activity against the promastigote form of leishmania major and exhibited IC50 value 0.98 ± 0.06 μM (Compound 10) as compared to amphotericin B (IC50 value 0.29 ± 0.05 μM). The synthesized compounds act as a potent intercalator of SS-DNA and insert themselves into the nitrogenous bases of the DNA resulting in hypochromism and bathochromic shift.

Active compounds from a diverse library of triazolothiadiazole and triazolothiadiazine scaffolds: Synthesis, crystal structure determination, cytotoxicity, cholinesterase inhibitory activity, and binding mode analysis

In an effort to identify novel cholinesterase candidates for the treatment of Alzheimers disease (AD), a diverse array of potentially bioactive compounds including triazolothiadiazoles (4a-h and 5a-f) and triazolothiadiazines (6a-h) was obtained in good yields through the cyclocondensation reaction of 4-amino-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thiol (3) with various substituted aryl/heteroaryl/aryloxy acids and phenacyl bromides, respectively. The structures of newly prepared compounds were confirmed by IR, (1)H and (13)C NMR spectroscopy and, in case of 4a, by single crystal X-ray diffraction analysis. The purity of the synthesized compounds was ascertained by elemental analysis. The newly synthesized conjugated heterocycles were screened for cholinesterase inhibitory activity against electric eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE). Among the evaluated hybrids, several compounds were identified as potent inhibitors. Compounds 5b and 5d were most active with an IC50 value of 3.09 ± 0.154 and 11.3 ± 0.267 μM, respectively, against acetylcholinesterase, whereas 5b, 6a and 6g were most potent against butyrylcholinesterase, with an IC50 of 0.585 ± 0.154, 0.781 ± 0.213, and 1.09 ± 0.156 μM, respectively, compared to neostigmine and donepezil as standard drugs. The synthesized heteroaromatic compounds were also tested for their cytotoxic potential against lung carcinoma (H157) and vero cell lines. Among them, compound 6h exhibited highest antiproliferative activity against H157 cell lines, with IC50 value of 0.96 ± 0.43 μM at 1mM concentration as compared to vincristine (IC50=1.03 ± 0.04 μM), standard drug used in this study.

Synthesis, cytotoxicity and molecular modelling studies of new phenylcinnamide derivatives as potent inhibitors of cholinesterases.

The present study reports the synthesis of cinnamide derivatives and their biological activity as inhibitors of both cholinesterases and anticancer agents. Controlled inhibition of brain acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) may slow neurodegeneration in Alzheimers diseases (AD). The anticholinesterase activity of phenylcinnamide derivatives was determined against Electric Eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE) and some of the compounds appeared as moderately potent inhibitors of EeAChE and hBChE. The compound 3-(2-(Benzyloxy)phenyl)-N-(3,4,5-trimethoxyphenyl)acrylamide (3i) showed maximum activity against EeAChE with an IC50 0.29 ± 0.21 μM whereas 3-(2-chloro-6-nitrophenyl)-N-(3,4,5-trimethoxyphenyl)acrylamide (3k) was proved to be the most potent inhibitor of hBChE having IC50 1.18 ± 1.31 μM. To better understand the enzyme-inhibitor interaction of the most active compounds toward cholinesterases, molecular modelling studies were carried out on high-resolution crystallographic structures. The anticancer effects of synthesized compounds were also evaluated against cancer cell line (lung carcinoma). The compounds may be useful leads for the design of a new class of anticancer drugs for the treatment of cancer and cholinesterase inhibitors for Alzheimers disease (AD).

Synthesis, cholinesterase inhibition and molecular modelling studies of coumarin linked thiourea derivatives

Alzheimers disease is among the most widespread neurodegenerative disorder. Cholinesterases (ChEs) play an indispensable role in the control of cholinergic transmission and thus the acetylcholine level in the brain is enhanced by inhibition of ChEs. Coumarin linked thiourea derivatives were designed, synthesized and evaluated biologically in order to determine their inhibitory activity against acetylcholinesterases (AChE) and butyrylcholinesterases (BChE). The synthesized derivatives of coumarin linked thiourea compounds showed potential inhibitory activity against AChE and BChE. Among all the synthesized compounds, 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(3-chlorophenyl)thiourea (2e) was the most potent inhibitor against AChE with an IC50 value of 0.04±0.01μM, while 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(2-methoxyphenyl)thiourea (2b) showed the most potent inhibitory activity with an IC50 value of 0.06±0.02μM against BChE. Molecular docking simulations were performed using the homology models of both cholinesterases in order to explore the probable binding modes of inhibitors. Results showed that the novel synthesized coumarin linked thiourea derivatives are potential candidates to develop for potent and efficacious acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors.

Synthesis, urease inhibition, antioxidant and antibacterial studies of some 4-amino-5-aryl-3H-1,2,4-triazole-3-thiones and their 3,6-disubstituted 1,2,4-triazolo[3,4-b]1,3,4-thiadiazole derivatives

A new series of 4-amino-5-aryl-3H-1,2,4-triazole-3-thiones, bearing various methoxybenzyl- and methoxyphenethyl groups, was synthesized by refluxing potassium hydrazinecarbodithioate salts in dilute aqueous solution of hydrazine hydrate. These salts were formed by the reaction of acid hydrazides and carbon disulfide in methanolic potassium hydroxide solution at 0-5 °C. 4-Amino-5-aryl-3H-1,2,4-triazole-3-thiones were condensed with different substituted aromatic acids to yield 3,6-disubstituted-1,2,4-triazolo[3,4-b]1,3,4-thiadiazoles. The structures of the synthesized compounds were characterized by infrared (IR), 1H and 13C nuclear magnetic resonance (NMR), elemental analysis and mass spectrometric (MS) studies. All the synthesized compounds were screened for their urease inhibition, antioxidant and antibacterial activities. Some compounds showed excellent urease inhibition activity, more than the standard drug. Others exhibited potent antioxidant activity. All the compounds showed significant antibacterial activities as compared to the standard drug.

Synthesis, urease inhibition, antioxidant, antibacterial, and molecular docking studies of 1,3,4-oxadiazole derivatives.

A series of eighteen 1,3,4-oxadiazole derivatives have been synthesized by treating aromatic acid hydrazides with carbon disulfide in ethanolic potassium hydroxide yielding potassium salts of 1,3,4-oxadiazoles. Upon neutralization with 1 N hydrochloric acid yielded crude crystals of 1,3,4-oxadiazoles, which were purified by recrystallization in boiling methanol. The synthesized 1,3,4-oxadiazoles derivatives were evaluated in vitro for their urease inhibitory activities, most of the investigated compounds were potent inhibitors of Jack bean urease. The molecular docking studies were performed by docking them into the crystal structure of Jack bean urease to observe the mode of interaction of synthesized compounds. The synthesized compounds were also tested for antibacterial and antioxidant activities and some derivatives exhibited very promising results.

Exploration of a library of triazolothiadiazole and triazolothiadiazine compounds as a highly potent and selective family of cholinesterase and monoamine oxidase inhibitors: design, synthesis, X-ray diffraction analysis and molecular docking studies

There is a high demand for the collection of small organic molecules (especially N-heterocycles) with diversity and complexity in the process of drug discovery. This need for privileged scaffolds in medicinal research gives an impetus for the development of nitrogen-containing compounds which are widely encountered in natural products, drugs and pharmaceutically active compounds. In this context, a diverse library of new triazolothiadiazole (4a–l) and triazolothiadiazine (5a–p) compounds was designed, synthesized and evaluated as potent and selective inhibitors of electric eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE) by Ellmans method using neostigmine and donepezil as standard inhibitors. Among the screened triazolothiadiazoles, 4j emerged as a lead candidate showing the highest inhibition with an outstanding IC50 value of 0.117 ± 0.007 μM against AChE, which is ∼139-fold greater inhibitory efficacy as compared to neostigmine, whereas 4k displayed ∼506-fold strong inhibition with IC50 of 0.056 ± 0.001 μM against BChE. In the triazolothiadiazine series, 5j and 5e depicted a clear selectivity towards EeAChE with IC50 values of 0.065 ± 0.005 and 0.075 ± 0.001 μM, respectively, which are ∼250- and ∼218-fold stronger inhibition as compared to neostigmine (IC50 = 16.3 ± 1.12 μM). In addition, the synthesized compounds were also tested for their monoamine oxidase (MAO-A and MAO-B) inhibition, where 4a from the triazolothiadiazole series delivered the highest potency against MAO-A with an IC50 value of 0.11 ± 0.005 μM which is ∼33-fold higher inhibition as compared to the standard inhibitor, clorgyline (IC50 = 3.64 ± 0.012 μM), whereas compound 5c from the triazolothiadiazine series turned out to be a lead inhibitor with an IC50 value of 0.011 ± 0.001 μM which is ∼330-fold stronger inhibition. Moreover, compounds 4b (triazolothiadiazole series) and 5o (triazolothiadiazine series) were identified as lead inhibitors against MAO-B. Molecular modelling studies were performed against human AChE and BChE to observe the binding site interactions of these compounds.

Antioxidant, Antimicrobial, and Free Radical Scavenging Potential of Aerial Parts of Periploca aphylla and Ricinus communis

Context. Many diseases are associated with oxidative stress caused by free radicals. Objective. The present study evaluated the in vitro antioxidant and antibacterial activities of various extracts of aerial parts of Periploca aphylla and Ricinus communis. Materials and Methods. In vitro antioxidant activities of the plant extract were determined by DPPH and NO scavenging method. Superoxide anion radical activity was measured by the reduction of nitro blue tetrazolium as compared with standard antioxidants. Total phenolic contents and antibacterial activities of these plants were determined by gallic acid equivalent (GAE) and serial tube dilution method, respectively. Results. Plants showed significant radical scavenging activity. The results were expressed as IC50. n-Propyl gallate and 3-t-butyl-4-hydroxyanisole were used as standards for antioxidant assay. All the extracts of both plants showed comparable IC50 to those of standards. Plants extract exhibited high phenolic contents and antibacterial activities were comparable with standard drug, Ciprofloxacin. Discussion and Conclusion. The present study provides evidence that Periploca aphylla and Ricinus communis prove to be potent natural antioxidants and could replace synthetic antioxidants. Plants can also be used against pathogenic bacterial strains.

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.