Medicinal Chemistry - Volume 18, Issue 7, 2022

Mannich bases identified by Professor Carl Mannich have been the most extensively explored scaffolds for more than 100 years now. The versatile biological roles that they play have promoted their applications in many clinical conditions. The present review highlights the application of Mannich bases as cytotoxic agents, categorizing them into synthetic, semisynthetic, and prodrugs classes, and gives an exhaustive account of the work reported in the last two decades. The methods of synthesis of these cytotoxic agents, their anti-cancer potential in various cell lines, and promising leads for future drug development have also been discussed. Structure-activity relationships, along with the targets on which these cytotoxic Mannich bases act, have been included as well.

Parkinson’s disease is a relatively common neurological disorder with incidence increasing with age. Since current medications only relieve the symptoms and do not change the course of the disease, therefore, finding disease-modifying therapies is a critical unmet medical need. However, significant progress in understanding how genetics underpins Parkinson's disease (PD) has opened up new opportunities for understanding disease pathogenesis and identifying possible therapeutic targets. One such target is leucine-rich repeat kinase 2 (LRRK2), an elusive enzyme implicated in both familial and idiopathic PD risk. As a result, both academia and industry have promoted the development of potent and selective inhibitors of LRRK2. In this review, we have summarized recent progress in the discovery and development of LRKK2 inhibitors as well as the bioactivity of several small-molecule LRRK2 inhibitors that have been used to inhibit LRRK2 kinase activity in vitro or in vivo.

Background: Reactive oxygen species (ROS) play a vital role in cell signaling when maintained at low concentrations. However, when ROS production exceeds the neutralizing capacity of endogenous antioxidants, oxidative stress is observed, which has been shown to contribute to neurodegenerative diseases such as Parkinson's disease (PD). PD is a progressive disorder characterized by the loss of dopaminergic neurons from the striatum, which leads to motor and nonmotor symptoms. Although the complex interplay of mechanisms responsible is yet to be fully understood, oxidative stress was found to be positively associated with PD. Despite active research, currently proposed regimens mainly focus on regulating dopamine metabolism within the brain, even though these treatments have shown limited long-term efficacy and several side effects. Due to the implication of oxidative stress in the pathophysiology of PD, natural antioxidant compounds have attracted interest as potential therapeutics over the last years, with a more favorable anticipated safety profile due to their natural origin. Therefore, natural antioxidants are currently being explored as promising anti-PD agents. Objective: In this mini-review, emphasis was given to presently studied natural antioxidant and neuroprotective agents that have shown positive results in PD animal models. Methods: For this purpose, recent scientific articles were reviewed and discussed, with the aim to highlight the most up-to-date advances on PD treatment strategies related to oxidative stress. Results: A plethora of natural compounds are actively being explored against PD, including kaemferol, icaritin, artemisinin, and α-bisabolol, with promising results. Most of these compounds have shown adequate neuroprotective ability along with redox balance restoration, normalized mitochondrial function, and limitation of oxidative damage. Conclusion: In conclusion, natural antioxidants may be the way forward to novel treatments against PD when the limitations of correct dosing and appropriate combinations are resolved.

Background: It is known that pyrrolidinone derivates belong to a class of biologically active compounds with a broad spectrum of biological actions. Nowadays, many scientists are making an effort in the discovery of more effective ways to eliminate reactive oxygen species (ROS) that cause oxidative stress or to eliminate the harmful microorganisms from the organism in humans. Therefore, pyrrolidinones seem to be great candidates for the research of this field. Methods: The antimicrobial activity of tested compounds was estimated by the determination of the minimal inhibitory concentration by the broth micro-dilution method against four species of bacteria and five species of fungi. The antioxidant activity was evaluated by free radical scavenging and reducing power. Results: Among the tested compounds, P22 showed marked antibacterial activity on Staphylococcus aureus with a MIC value of 0.312 mg/mL. Maximum antifungal activity with MIC value 0.625 mg/mL was shown by P23 and P25 compounds against Trichophyton mentagrophytes. Tested samples showed a relatively strong scavenging activity on DPPH radical (IC50 ranged from 166.75- 727.17 μg/mL). The strongest DPPH radical scavenging activity was shown by P3 compound with an IC50 value of 166.75 μg/mL. Moreover, the tested compounds had effective reducing power. Compounds P3, P10, and P13 showed the highest reducing power than those from the other samples. Results of the interactions between DNA and P3 indicated that P3 had the affinity to displace EB from the EB-DNA complex through intercalation [Ksv = (1.4 ± 0.1) × 10⁵ M^-1], while Ka values obtained via titration of BSA with P23 or P25 [Ka = (6.2 ± 0.2) and (5.0 ± 0.2) × 10⁵ M^-1] indicate that the notable quantity of the drug can be transmitted to the cells. Conclusion: Achieved results indicate that our compounds are potential candidates for use as medicaments.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are the commonly used therapeutic interventions of inflammation and pain that competitively inhibit the cyclooxygenase (COX) enzymes. Several side effects like gastrointestinal and renal toxicities are associated with the use of these drugs. The therapeutic anti-inflammatory benefits of NSAIDs are produced by the inhibition of COX-2 enzymes, while undesirable side effects arise from the inhibition of COX-1 enzymes. Objective: In the present study, a new series of 2-substituted benzoxazole derivatives 2(a-f) and 3(ae) were synthesized in our lab as potent anti-inflammatory agents with outstanding gastro-protective potential. The new analogs 2(a-f) and 3(a-e) were designed depending upon the literature review to serve as ligands for the development of selective COX-2 inhibitors. Methods: The synthesized analogs were characterized using different spectroscopic techniques (FTIR, ¹HNMR, ¹³CNMR) and elemental analysis. All synthesized compounds were screened for their binding potential in the protein pocket of COX-2 and evaluated for their anti-inflammatory potential in animals using the carrageenan-induced paw edema method. Further 5 compounds were selected to assess the in vivo anti-ulcerogenic activity in an ethanol-induced anti-ulcer rat model. Results: Five compounds (2a, 2b, 3a, 3b and 3c) exhibited potent anti-inflammatory activity and significant binding potential in the COX-2 protein pocket. Similarly, these five compounds demonstrated a significant gastro-protective effect (**p<0.01) in comparison to the standard drug, Omeprazole. Conclusion: Depending upon our results, we hypothesize that 2-substituted benzoxazole derivatives have excellent potential to serve as candidates for the development of selective anti-inflammatory agents (COX-2 inhibitors). However, further assessments are required to delineate their underlying mechanisms.

Aim: The reactions were carried out by one pot three-component synthesis, 3- cyanoacetylindole (1) on reaction with aromatic aldehydes (2) and β-naphthol (3) in an aqueous medium in the presence of L-proline as a catalyst under reflux for 30 min, resulting in (3-amino-1- phenyl-1H-benzo[f]chromen-2-yl) (1H-indol-3-yl)methanone (4). The method has many advantages like short reaction times, good yields, and simple workup procedure, besides being green in nature. Pharmacological evaluation of title compounds was done for anti-inflammatory and analgesic activities. Anti-inflammatory activity was carried carrageenan-induced paw edema model in which indomethacin was used as standard and analgesic activity was evaluated by eddy's hot plate method using diclofenac as standard drug. Background: Benzopyrans or chromenes are an important class of heterocyclic compounds due to their broad spectrum of biological activity and a wide range of applications in medicinal chemistry. The chromene moiety is found in various natural products with interesting biological properties. Chromenes constitute the basic backbone of various types of polyphenols and are widely found in alkaloids, tocopherols, flavonoids, and anthocyanins. Indoles are omnipresent in various bioactive compounds like alkaloids, agrochemicals, and pharmaceuticals. Objective: The objective of this study is to synthesize one-pot stepwise Green synthesis, antiinflammatory and analgesic activities of 3-amino-1-phenyl-1H-benzo[f]chromen-2-yl) (1H-indol-3- yl) methanones. Methods: The acute anti-inflammatory effect was evaluated by carrageenan-induced mice paw edema (Ma Rachchh et al., 2011). Edema was induced by injecting carrageenan (1% w/v, 0.1 ml) in the right hind paw of mice. The test compounds 1-12, indomethacin (10 mg/kg), and the vehicle were administered orally one hour before injection of carrageenan. Paw volume was measured with a digital plethysmometer at 0, 30, 60, 90, 120 min after injection. Percentage increase =A-B/ A *100. Results: Carrageenan induced paw edema model was used for anti-inflammatory activity in which animals treated with standard (indomethacin) and test compounds showed a significant decrease in the paw edema. Analgesic activity was estimated using Eddy’s hot plate method; animals were treated with standard (diclofenac) and test compounds showed a significant increase in the reaction time. Conclusion: A green, one-pot, step-wise and three-component synthesis of 3-amino-1-phenyl-1Hbenzo[ f]chromen-2-yl) (1H-indol-3-yl) methanone was achieved by using water as a solvent, Lproline as catalyst under reflux conditions. The reactions were carried out in eco-friendly conditions with shorter reaction times, easier workup, and high yields. Anti-inflammatory activity was evaluated by carrageenan-induced paw edema model, where significant anti-inflammatory activity is shown by all the test compounds 4(a-l) compared to standard drug. Analgesic activity was studied by Eddy’s Hot plate method and Test compounds 4e, 4f, 4h, 4i, 4j, 4k, 4l showed significant activities compared to the reference drug.

Aims: To synthesize bis-1,3,4-oxadiazole derivatives as novel and potential urease inhibitors. Background: Despite many important biological activities associated with oxadiazoles, they are still neglected by medicinal chemists for their possible urease inhibitory activity. Keeping in view the countless importance of urease inhibitors, we have synthesized a new library of substituted bisoxadiazole derivatives (1-21) to evaluate their urease inhibitory potential. Objective: The aim includes the synthesis of substituted bis-oxadiazole derivatives (1-21) in order to evaluate their urease inhibitory potential. Methods: Bis-1,3,4-oxadiazole derivatives 1-21 were synthesized through sequential reactions using starting material isophthalic acid. Esterification reaction was done by refluxing in methanol for 2 h in the presence of the catalytic amount of concentrated H2SO4 till dissolution. In the second step, dimethyl isophthalate and hydrazine hydrate in excess (1:5) were refluxed in methanol to afford isophthalic dihydrazide. Then, isophthalic dihydrazide was treated with different substituted benzaldehydes in a 1:2 ratio under acidic conditions. Results: In vitro urease, the inhibitory activity of the synthesized compounds was evaluated and the results demonstrated good activities with IC50 values in the range of 13.46 ± 0.34 to 74.45 ± 3.81 μM as compared to the standard thiourea (IC50 = 21.13 ± 0.415 μM). Most of the compounds were found to be more potent than the standard. The structure-activity relationship (SAR) suggested that the variations in the inhibitory activities of the compounds were due to different substitutions. Furthermore; in silico study was also performed. Conclusion: Current study identified a new class of urease inhibitors. All synthetic compounds 1-21 showed potent as well as good to moderate urease inhibitory activities except 3. SAR suggested that hydroxy-bearing analogs were identified exceptionally well. Molecular docking revealed many important interactions made by compounds with the active site of the urease enzyme.