Medicinal Chemistry - Volume 17, Issue 10, 2021

Background: Several quinones are on the pharmaceutical market as drugs for the treatment of several diseases. Objective: The aim of this review was to provide an overview of the quinones that have become drugs for several therapeutic applications. Methods: We have comprehensively and critically discussed all the information available in the literature about quinone-based drugs. Results: In this review, the various aspects of the chemistry and biochemistry of these drugs are highlighted, including their repositioning, drug combination and their new uses. Conclusion: A number of studies related to quinone drugs for different pharmaceutical uses show that the interest in new applications is still increasing in recent years.

Background: Alzheimer’s Disease (AD) is one of the most common neurodegenerative disorders, characterized by memory deficits and cognitive impairment. Acetylcholinesterase inhibitors, NMDA receptor antagonists and nootropic agents are used clinically, but they have only symptomatic efficacy, attributed to the multifactorial character of AD. The multi-target directed compound approach is gaining attention and has been under investigation lately. Objective: This review selects several research articles, which describe the design, synthesis and biological evaluation of multi-targeting molecules combining antioxidant or/and anti-inflammatory properties. Compounds with these properties are expected to be beneficial in the treatment of AD. Methods: This review summarizes the pathobiochemistry of AD as well as the role of oxidative stress and inflammation in the progression of neurodegeneration. It presents novel compounds with antioxidant or/and anti-inflammatory activity that have been tested for their efficacy in neurodegenerative disorders. Results: Various researchers have taken advantage of the multi-targeting drug approach in order to design molecules which may be developed as useful agents for the treatment of neurodegeneration. Conclusion: The multi-targeting compound approach is a developing therapeutic strategy for multifactorial diseases, such as AD, and can offer effective agents for their radical treatment.

Background: Targeted therapies acting on specific molecular targets in cancer cells with better curative efficacy and lower toxicity have come into prominence for the management of nonsmall cell lung cancer (NSCLC) and colorectal cancer (CRC). COX-2 stands out as a plausible target for anticancer agents due to its pivotal role in tumor initiation, progression and invasion. Objectives: Due to the importance of triazolothiadiazine scaffold in targeted anticancer drug discovery, the aim of this work is the design of new triazolothiadiazines as potential anticancer agents for the targeted therapy of NSCLC and CRC. Methods: New triazolo[3,4-b]-1,3,4-thiadiazines (2a-g) were synthesized via the ring closure reactions of 2-bromo-1-arylethanones with 4-amino-5-((5-methoxy-2-methyl-1H-indol-3-yl)methyl)-2,4- dihydro-3H-1,2,4-triazole-3-thione (1), which was obtained via the solvent-free reaction of 5- methoxy-2-methyl-3-indoleacetic acid with thiocarbohydrazide. MTT assay was performed to determine their cytotoxic effects on A549 human lung adenocarcinoma, Caco-2 human colorectal adenocarcinoma and CCD-19Lu human lung fibroblast cells. The most potent compounds were evaluated for their effects on apoptosis, caspase-3, mitochondrial membrane potential, cell cycle, ultrastructural morphological changes and COX-2 in A549 and Caco-2 cells. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrödinger’s Maestro molecular modeling package. Results: 6-(4-Chlorophenyl)-3-[(5-methoxy-2-methyl-1H-indol-3-yl)methyl]-7H-[1,2,4]triazolo[3,4- b][1,3,4]thiadiazine (2e) was the most potent and selective anticancer agent in this series against A549 and Caco-2 cell lines. Compound 2e induced early apoptosis, caused mitochondrial membrane depolarization and arrested cell cycle at G0/G1 phase in A549 cells. On the other hand, compound 2e triggered intrinsic apoptotic pathway involving caspase-3 activation in Caco-2 cells. Compound 2e caused apoptotic morphological changes in both cancer cell lines. The cytotoxic and apoptotic effects of this compound on CRC were found to be related to its selective COX-2 inhibitory activity. According to molecular docking studies, compound 2e showed good affinity to the active site of COX-2 (PDB code: 4COX). Based on in silico ADME studies, the compound is predicted to possess a favorable ADME profile. Conclusion: According to in vitro and in silico studies, compound 2e was identified as a potential orally bioavailable anticancer agent for COX-2-targeted therapy of CRC.

Background: Six N-acyl derivatives of aminocombretastatin A-4 have been synthesized and evaluated according to their interaction with tubulin and as c-Myc downregulators. Aims: In search of new promising anti-cancer agents. Objective: This study is focused on the synthesis and the biological evaluation of N-acyl derivatives of aminocombretastatin A-4 (CA-4). Docking studies were carried out to find out whether the synthetic derivatives could bind to tubulin at the colchicine site in a conformation similar to that of CA- 4. The synthetic derivatives' effect on the proliferation of several cancer cells and non-cancer cells has been measured. Their effect on tubulin polymerization, cell cycle distribution, the microtubule network and c-Myc expression has also been evaluated. Methods: A set of six N-acyl derivatives was achieved by means of a peptide-type coupling of aminocombretastatin A-4 and the corresponding carboxylic acid. The synthetic compounds' ability to inhibit cell proliferation was measured by MTT assay against three human carcinoma cell lines (colorectal HT-29, lung A549, and breast adenocarcinoma MCF-7) and one non-tumor cell line (HEK- 293). Turbidimetry time-course measurements evaluated the inhibition of tubulin polymerization. The action of the synthetic derivatives on cell cycle distribution was measured by flow cytometry and their effects on the microtubule network were determined by immunofluorescence microscopy. Finally, the downregulation of the synthetic derivatives on c-Myc protein was quantified by ELISA assay, while the effect on c-Myc gene was measured by RT-qPCR analysis. Results: Derivatives bearing pentanoyl (compound 2), hexanoyl (compound 3), and heptanoyl (compound 4) side chains show anti-proliferative activities on the HT-29 line in the low nanomolar range, with values similar to that exhibited by AmCA-4 but far exceeding those of CA-4. Compounds 1 (butanoyl side chain) and 2-3 inhibit tubulin polymerization in vitro in a manner similar to that of CA-4 and AmCA-4 whereas compounds 4, 5 (octanoyl side chain) and 6 (dodecanoyl side chain) may be considered as partial inhibitors of tubulin polymerization. While all derivatives are able to accumulate cells in G2/M phase, compounds with the longest acyl chains (5 and 6) are the least active ones in this particular action. Moreover, compounds 2-3 were the most active ones as c-Myc downregulators. Conclusion: Our studies show that the most active compounds in the disruption of the microtubule network are also the most potent ones in the downregulation of c-Myc expression. Other: Compounds 2 and 3 are good candidates for in vivo studies as they combine the best antimitotic and c-Myc downregulation activities at low doses.

Background: Bone loss is the most common reason for broken bones among the elderly. An ideal agent for the treatment of bone loss should have both osteoclast inhibitory and osteoblast stimulatory functions. Leucine-rich repeat kinase 1 (LRRK1) is a novel target for alternative antiresorptive drugs to treat osteoporosis and osteoporotic fractures. Recently a chemical IN04, Methyl 3-[({([5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-thio}-acetyl)-amino]-benzoate, has been identified as a potential LRRK1 inhibitor. Objective: The aim of this work is to investigate how the chemical IN04 interacts with LRRK1 and inhibits its activity. Methods: A structural model of the LRRK1 kinase domain was constructed with SWISS-MODEL. The human protein kinase ROCO4 (PDB ID: 4YZN) was chosen as the template based on sequence homology, structural and phylogenetic analysis. In addition, a homology model of the LRRK1 ROC domain was also prepared based on the LRRK2 ROC domain structure (PDB ID: 2ZEJ). The interactions of IN04 with the active sites in the LRRK1 kinase domain and ROC domain were investigated by SwissDock. Results: IN04 was docked into the active site of the LRRK1 kinase domain with similar interactions as ATP comparable to the ligand bound to homologous kinases. Many rational binding modes of IN04 to LRRK1 kinase domain were investigated and the most likely binding pose containing multiple hydrogen bonds and a salt bridge was discovered. However, IN04 cannot fit into the GDP-binding site of the ROC domain. Conclusion: Chemical IN04 inhibits LRRK1 by binding to the active site of the kinase domain but not the ROC domain

Background: Sigma receptors (σRs), initially classified as an additional class of opioid receptors, are now recognized as a unique entity with no homology to opioid receptors divided into two distinct subtypes, namely σ1R and σ2R. σ1R-targeting ligands have been conceived and explored for the treatment of various neurodegenerative disorders and neuropathic pain. Activation of the σ2R appears to be involved in the regulation of cellular proliferation and cell death. Objective: Up to now, the rational design of novel σ1R ligands was efficiently guided by computational methods, especially relying on homology modeling studies. Conversely, the limited number of in silico studies was applied in the search of σ2R-targeting compounds. Herein we explored several series of σ1R ligands, by computational methods, featuring variable selectivity profile towards σ1R and σ2R in order to gain useful information guiding the rational design of more selective ligands. Methods: Based on the recent X-ray crystallographic structure of the human σ1R, in-depth molecular docking studies on different series of σR ligands have been performed. These calculations have been followed by molecular dynamic simulations (MD) and two pharmacophore analyses, taking into account the activity levels towards σ1R and σ2R. Results: Structure-based studies revealed key contacts to be achieved in order to guide selectivity of σ1R-targeting compounds while the two pharmacophore models described the main features turning into effective σ1R or σ2R ligands. Conclusion: The applied computational approach allowed a more comprehensive exploration of the structure-activity relationship (SAR) within the herein analyzed σR ligands, deriving useful guidelines for the rational design of more selective compounds.

Background: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by demyelination of neurons and neurodegeneration. Current MS therapies ameliorate inflammatory damage but are unable to address the degenerative aspects of the disease. Objective: In this report, we evaluate the ability of amide-based dithiolethiones (DTTs) to suppress neuroinflammation in microglia and increase anti-oxidant capacity in neuron-like cells. Methods: A series of amide-containing DTTs were designed, synthesized, and assayed for the ability to suppress pro-neuroinflammatory cytokines IL-12p40 and IL-23p19 induced by LPS in the BV2 microglial cell line. Lead analog 2c was identified and further characterized. Results: Structure-activity data revealed tolerance towards a variety of amides. Morpholine analog 2c dose-dependently reduced various other inflammatory cytokines and mediators, including TNF, IL-6, IL-1β, NOS2, and COX2. Additionally, 2c elevated cellular levels of glutathione in SH-SH5Y neuronal cell line. Furthermore, mechanistic studies showed that 2c increased the expression of antiinflammatory Nrf2 and HMOX proteins. Conclusion: The combination of anti-neuroinflammatory and anti-oxidant activities of amide-based DTTs suggests that they are promising agents for the treatment of both demyelination and neurodegeneration in MS.

Background: About 50 million epileptic cases worldwide and 12 million in India are reported. Currently, available drugs yield adequate control of seizure in 60-70% of patients and show many toxic effects. These actualities provoked the search for novel, more efficacious and safer anticonvulsants. Objective: The concatenation of 2-(1,3-benzodioxol-5-yloxy)-N'-[substituted]-acetohydrazides SA 1- 10 was designed by molecular hybridization, optimized by computational study and synthesized with the objective of obtaining a prototype of potent anticonvulsant molecules especially active against partial seizures. Methods: Computational study was performed to calculate the pharmacophoric design, projection of the pharmacokinetic parameters and docking scores of the titled compounds with molecular targets of epilepsy. The anticonvulsant activity was ascertained by 6 Hz psychomotor seizure test. Minimal motor impairment showing neurotoxicity was assessed using the Rotarod test. Results: Titled compounds possessed the indispensable elements of pharmacophore and displayed good binding affinity with molecular targets of epilepsy, such as GABA (A) alpha-1 & delta receptor, glutamate receptor, Na⁺/H⁺ exchanger and GABA- aminotransferase in docking studies. The most potent compound of the concatenation was 2-(1,3-benzodioxol-5-yloxy)-N'-[4-(4- chlorophenoxy)benzylidene]-acetohydrazide SA 4, showing 100% protection at four different time points with ED50 value 146.8 mg/kg at a TPE of 1 h in mice. Conclusion: The protection shown in 6 Hz test is implicated as the compound's ability to control partial seizures. Thus, the titled compounds can be considered as potential prototype candidates for antiepileptic therapy against partial seizures.

Alzheimer’s disease is one of the most common neurodegenerative disorder afflicting a large mass of population. BACE-1 (β-secretase) is an aspartyl protease of the amyloidogenic pathway considered responsible for Alzheimer’s disease (AD). Since it catalyzes the rate-limiting step of Aβ-42 production from amyloid precursor protein (APP), its inhibition is considered a viable therapeutic strategy. We have reported the design of small molecular weight compounds supposed to be blood brain permeable as BACE-1 inhibitors. The clue for the design of this series is drawn from the previously designed series from our research group. Objective: Design and synthesis of 2,4,6-substituted pyrimidine derivatives has been reported. In vitro FRET-based screening of synthesized derivatives was performed to evaluate the BACE-1 inhibition profile. Methods: Based on the docking simulation studies, a library of derivatives was designed, synthesized and evaluated for BACE-1 inhibition in-vitro. The docking studies were performed on Glide (Schrodinger suite) and Molegro virtual docker. Theoretical toxicity was predicted using Osiris Property Explorer. The synthesized compounds were tested for BACE-1 inhibition using in vitro assay based on Fluorescence Resonance Energy Transfer technique. The percent inhibition was calculated as a measure of activity. Results: The designed compounds revealed strong interactions with the desired amino acids of BACE-1 active sites. The aromatic rings placed at the fourth and sixth position of the pyrimidine ring occupied S1 and S3 substrate-binding clefts while the amino group formed hydrogen bonding interactions with Asp32 and Asp228. In silico data ensured that the compounds were orally bioavailable and brain permeable. The in vitro testing showed that the compounds inhibited BACE-1 at 10μM concentration. Conclusion: Compounds substituted with m-benzyloxy on one aromatic ring and o,p-di-chloro on another aromatic ring displayed maximum BACE-1 inhibition. Compound 2.13A displayed high docking score and was found to be most potent with IC50 of 6.92μM. The series displayed a good correlation between the docking score and BACE-1 inhibition profile.

Background: Malaria is one of the most devastating parasitic diseases, yet the discovery of antimalarial agents remains profoundly challenging. Very few new antimalarials have been developed in the past 50 years, while the emergence of drug-resistance continues to appear. Objective: This study focuses on the discovery, design, synthesis, and antimalarial evaluation of 3- cinnamamido-N-substituted benzamides. Methods: In this study, a screening of our compound library was carried out against the multidrugsensitive Plasmodium falciparum 3D7 strain. Derivatives of the hit were designed, synthesized and tested against P. falciparum 3D7 and the in vivo antimalarial activity of the most active compounds was evaluated using the method of Peters’ 4-day suppressive test. Results: The retrieved hit compound 1 containing a 3-cinnamamido-N-substituted benzamide skeleton showed moderate antimalarial activity (IC50 = 1.20 μM) for the first time. A series of derivatives were then synthesized through a simple four-step workflow, and half of them exhibited slightly better antimalarial effect than the precursor 1 during the subsequent in vitro assays. Additionally, compounds 11, 23, 30 and 31 displayed potent activity with IC50 values of approximately 0.1 μM, and weak cytotoxicity against mammalian cells. However, in vivo antimalarial activity is not effective, which might be ascribed to the poor solubility of these compounds. Conclusion: In this study, the phenotypic screen of our compound library resulted in the first report of a 3-cinnamamide framework with antimalarial activity and 40 derivatives were then designed and synthesized. Subsequent structure-activity studies showed that compounds 11, 23, 30 and 31 exhibited the most potent and selective activity against the P. falciparum 3D7 strain with IC50 values around 0.1 μM. Our work herein sets another example of phenotypic screen-based drug discovery, leading to potentially promising candidates of novel antimalarial agents once given further optimization.