Letters in Drug Design & Discovery - Volume 18, Issue 4, 2021

Atherosclerosis, a cardiovascular disease, is at the top of the list among the diseases leading to death. Although the biochemical and pathophysiological cascades involved within the development of atherosclerosis have been identified clearly, its nature is quite complex to be treated with a single agent targeting a pathway. Therefore, many natural and synthetic compounds have been suggested for the treatment of the disease. The majority of the drugs employed target one of the single components of the pathological outcomes, resulting in many times less effective and longterm treatments. In most cases, treatment options prevent further worsening of the symptoms rather than a radical treatment. Consequently, the current review has been prepared to focus on the validated and non-validated targets of atherosclerosis as well as the alternative treatment options such as hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, acyl-CoA cholesterol acyl transferase (ACAT) inhibitors, lipoprotein lipase stimulants, bile acid sequestrants, and some antioxidants. Related to the topic, both synthetic compounds designed employing medicinal chemistry skills and natural molecules becoming more popular in drug development are scrutinized in this mini review.

Background: The development of antibiotic resistance in bacteria is a matter of global concern due to the exceptionally high morbidity and mortality rates. The outer membrane of most gram-negative bacteria acts as a highly efficient barrier and blocks the entry of the majority of antibiotics, making them ineffective. The Bam complex, β-barrel assembly machinery complex, contains five subunits (BamA, B, C, D, E), which plays a vital role in folding and inserting essential outer membrane proteins into the membrane, thus maintaining outer membrane integrity. BamA and BamD are essential subunits to fulfill this purpose. Therefore, targeting this complex to treat antibiotic resistance can be an incredibly effective approach. Natural bacterial pigments like violacein, phytochemicals like withanone, semasin, and several polyphenols have often been reported for their effective antibiotic, antioxidant, anti-inflammatory, antiviral, and anti-carcinogenic properties. Objective: Structural inhibition of the Bam complex by natural compounds can provide safe and effective treatment for antibiotic resistance by targeting outer membrane integrity. Methods: In-silico ADMET and molecular docking analysis was performed with ten natural compounds, namely violacein, withanone, sesamin, resveratrol, naringenin, quercetin, epicatechin, gallic acid, ellagic acid, and galangin, to analyse their inhibitory potential against the Bam complex. Results: Docking complexes of violacein gave high binding energies of -10.385 and -9.46 Kcal/mol at C and D subunits interface and at A subunits of the Bam complex, respectively. Conclusion: Henceforth, violacein can be an effective antibiotic against to date reported resistant gram-negative bacteria by inhibiting the Bam complex of their outer membrane. Therefore the urgent need for exhaustive research in this concern is highly demanded.

Background: Second generation or “atypical” antipsychotics demonstrate an improved therapeutic profile over conventional neuroleptics. These are effective in both positive and negative symptoms of the disease and have a lower propensity to induce adverse symptoms. Objective: The main objective of the research was in silico design and synthesis of potential atypical antipsychotics with combined antiserotonergic / antidopaminergic effect. Methods: A one pot synthesis of aryl substituted imidazole derivatives was carried out in green solvent PEG-400 and the prepared compounds were evaluated for atypical antipsychotic activity in animal models for dopaminergic and serotonergic antagonism. The compounds were designed based on their 3D similarity studies to standard drugs and in silico (docking studies) with respect to 5-HT2A and D2 receptors. Results: Results from the docking studies with respect to 5-HT2A and D2 receptors suggested a potential atypical antipsychotic profile for the test compounds. Theoretical ADME profiling of the compounds based on selected physicochemical parameters suggested an excellent compliance with Lipinski’s rules. The potential of these compounds to penetrate the blood brain barrier (log BB) was computed through an online software program and the values obtained for the compounds suggested a good potential for brain permeation. Reversal of apomorphine induced mesh climbing behaviour coupled with inactivity in the stereotypy assay indicates antidopaminergic effect and a potential atypical profile for the test compounds 1-5. Further, the activity of compounds in DOI assay indicated a 5-HT2 antagonistic profile (5-HT2 antagonism). Conclusion: Compound 5 emerged as important lead compound showing combined antidopaminergic and antiserotonergic (5-HT2A) activity with a potential atypical antipsychotic profile.

Background: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has attracted worldwide attention due to its high infectivity and pathogenicity. Objective: The purpose of this study is to develop drugs with therapeutic potentials for COVID-19. Methods: we selected the crystal structure of 3CL pro to perform virtual screening against natural products in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Then, molecular dynamics (MD) simulation was carried out to explore the binding mode between compounds and 3CL pro. Results and Discussion: A total of 6 candidates with good theoretical binding affinity to 3CL pro were identified. The binding mode after MD shows that hydrogen bonding and hydrophobic interaction play an important role in the binding process. Finally, based on the free binding energy analysis, the candidate natural product Gypenoside LXXV may bind to 3CL pro with high binding affinity. Conclusion: The natural product Gypenoside LXXV may have good potential anti-SARS-COV-2 activity.

Background: Peripherally tetrasubstituted cobalt(II), titanium(IV), manganese(III) phthalocyanines carrying redox-active metal centers were previously synthesized. Metallophthalocyanines (MPcs) exhibited the potential to use in medicinal applications due to biological activities, such as antibacterial, antioxidant and enzyme inhibition. Objective: This study's aim was to evaluate the previously synthesized metallophthalocyanines in terms of carbonic anhydrase inhibition, antioxidant, and antimicrobial activities. Methods: Carbonic anhydrase activity was assayed by following esterase activity. The antibacterial activity was tested by the disc diffusion method against eight bacteria. The antioxidant activity was determined by two common methods, 2,2-diphenyl-1-picrylhydrazyl (DPPH•) radical scavenging and ferric ion (III) reducing/antioxidant power (FRAP) assays. Results: In this study, the inhibition potential of the metallophthallocyanines against carbonic anhydrase (CA) enzyme, which is important for treatments of many disorders, was evaluated. The metallophthalocyanines showed high CA inhibitory activity with IC50 values in the range of 74-317 nM, which was similar or better when compared with the standard CA inhibitors sulfanilamide and acetazolamide. In addition, antibacterial and antioxidant activities were determined. The metallophthallocyanines exhibited moderate antibacterial activity, especially against S. aureus and S. epidermis. The antioxidant activities of the compounds in both tests were quite high, even exceeding the standards Trolox and BHT, with SC50 values of 0.0048-0.0257 and TEAC values of 1143.3- 1543.7 μM, being 2 to 73 fold better activity. Conclusion: In conclusion, all three metallophthalocyanines exhibit excellent carbonic anhydrase and antioxidant potential and deserve further interest for the synthesis of new derivatives.

Background: Recently, researchers have been warning about the increased mortality of the various cancer types. Also, the lung adenocarcinoma and the glioma types are burning issues for world's health due to late or wrong diagnosis and/or insufficient treatment methods. For this purpose, our research group designed and synthesized novel 4,5-dimethyl thiazole-hydrazone derivatives which were tested against cancer and normal cell lines to understand the structureactivity relationship (SAR). Methods: The lead compounds were obtained by reacting 2-(substituted aryl-2-ylmethylene) hydrazin-1-carbothioamide with 3-chloro-2-butanone derivatives. The structural elucidation of the compounds was performed by ¹H-NMR, ¹³C-NMR, and LC/MS-IT-TOF spectral and elemental analyses. The synthesized compounds were tested in vitro for the anticancer activity against A549 human lung adenocarcinoma and C6 rat glioma cells and investigated for which pathway to induce cell death. Also, the docking study of the active compounds was achieved to understand the SAR. Results: The targeted compounds (2a-2l) were synthesized successfully above 70% yields, and the analysis findings proved their purity. In general, the results of activity studies displayed significant effects against at least one cell line, except compounds 2e (indol-3-yl) and 2h (4-dimethylaminophenyl). Furthermore, compounds 2b and 2f displayed potential anticancer activity. With the help of molecular docking study, a potential selectivity of compound 2f was observed for type II protein kinase. On the other hand, compound 2b interacted with the active site nearly the same as Dasatinib. Therefore, these two compounds could be used as a base on developing selective anticancer drugs. Conclusion: Pyridin-2-yl (2b) derivative was found to be a favorable molecule with high anticancer potency against C6 and A549 cell lines. Additionally, 1-naphthyl (2f) derivative was a worthy compound for potential selectivity. In future studies, it will be our priority to focus on developing derivatives of these two compounds (2b and 2f) and elucidate their mechanisms.

Aim: To design, synthesis and in vitro evaluation of 4-oxo-6-substituted phenyl-2- thioxo1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives as HIV integrase strand transfer inhibitors. Background: Human immunodeficiency virus-1 (HIV-1), a member of retroviridae family, is the primary causative agent of acquired immunodeficiency syndrome (AIDS). Three enzymes viz: integrase (IN), reverse transcriptase (RT) and protease play important role in its replication cycle. HIV-1 integrase is responsible for the incorporation of viral DNA into human chromosomal DNA by catalyzing two independent reactions, 3′-processing (3′-P) and strand transfer (ST), which are observed as the “point of no-return” in HIV infection. Objective: To develop inhibitors against HIV integrase strand transfer step. Methods: Our previous results indicated that tetrahydro pyrimidine-5-carboxamide derivatives are potent HIV-1 IN inhibitors (unpublished results from our laboratory). Taking clue from above studies and our own experience, we hypothesized 4-oxo-6-substituted phenyl-2-thioxo1,2,3,4- tetrahydropyrimidine-5-carbonitrile analogues (14a to 14n) as inhibitors of HIV-1 Integrase strand transfer. Prototype compound 14 can be viewed as hybrid structure having characteristics of dihydropyrimidine derivatives 10-12 and tyrphostin 13. Results: A total of fourteen derivatives of 4-oxo-6-substituted phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine- 5-carbonitrile (14a-14n) were synthesized and evaluated using HIV-1 Integrase Assay Kit (Xpressbio Life Science Products, USA). The percentage inhibition of all compounds was investigated at 10 μM concentration and IC50 value of few highly active compounds was studied. The obtained results were validated by in silico molecular docking study using Glide (maestro version 9.3, Schrödinger suite) in extra precision (XP) mode. Conclusion: Fourteen 4-oxo-6-substituted phenyl-2-thioxo 1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues were synthesized and evaluated for HIV-1 IN inhibitory activity. Three compounds 14a, 14e, and 14h exhibited significant percentage inhibition of HIV-1 IN. There was good in vitro - in silico correlation. However, none of the derivative was active against HIV-1 and HIV-2 below their cytotoxic concentration. It needs to be seen whether these compounds can be explored further for their anti-HIV or cytotoxic potential.

Background: The benzothiazole and its derivatives reported an extremely crucial duty in the progress of commercially important intermediary molecules, which are wanted for the manufacturing of various pharmacologically active agents. Introduction: As a necessary element of ongoing examination for the synthesis of new nonsteroidal anti-inflammatory agents (NSAIDs), a number of new benzothiazole derivatives were taken under consideration for the synthesis and were computationally studied along with their biological activity. Methods: Obtainable benzothiazole derivatives were synthesized by the condensing of 2-(4- aminophenoxy)-N-(benzo[d]thiazol-2-yl)acetamide with substituted acetophenones in ethanol in the presence of a catalytic amount of glacial acetic acid. The structures of newly synthesized compounds were characterized by IR, NMR spectroscopy and elemental analysis techniques. Several molecular properties of these derivatives were computed in order to estimate their drug like candidates. Molecular docking was performed to these synthesized derivatives with particular reference to cyclooxygenase-2 (COX-2) enzyme. The synthesized derivatives were screened for their biological activity, including analgesic and anti-inflammatory activity as COX-2 inhibitors. Results: From all data, it established that among all target compounds, S-4 (N-(benzo[d]thiazol- 2-yl)-2-(4-((1-(3-nitrophenyl)ethylidene)amino)phenoxy)acetamide) displayed the highest antiinflammatory and analgesic effects. Conclusion: All these findings recommended that S-4 might be utilized as a promising new lead compound for Nonsteroidal anti-inflammatory drug (NSAIDs) development.

Background: Trypanosomiasis is a widespread zoonotic disease and the existing drugs are not enough to prevent and treat it. Objective: This study aimed to build a quantitative structure-activity relationship model by the chemical structures of a class of thiazolidone/thiazolidamide based hybrids. The model was used to screen new antitrypanosomal agents and predict the properties of composite molecules. Methods: All compounds were randomly divided into a training set and a test set. A large number of descriptors were calculated by the software, then some of the best descriptors were selected to build the models. The linear model was built by the heuristic method and the nonlinear model was built by gene expression programming method. Results: In the heuristic method, the correlation coefficients ,R², R²cv, F and S² were 0.581, 0.457, 14.053 and 15.311, respectively. In gene expression programming, the R² and S² were 0.715, 10.997 in the training set and 0.617, 22.778 in the test set. The results showed that the relative number of S atoms and the minimum bond order of an H atom had a significant positive contribution to IC50. Meanwhile, the relative number of double bonds and the count of hydrogen-bonding acceptor sites had a great negative impact on IC50. Conclusion: Both the heuristic method and gene expression programming had a good predictive performance. By contrast, the gene expression programming method fitted well with the experimental values and it was expected to be beneficial in the synthesis of new antitrypanosomal drugs.