Anti-Infective Agents - Volume 20, Issue 5, 2022

Background: Heterocyclic scaffolds have gained exceptional devotion in recent years due to their marked utility in the bio-organic field. Among these, pyrazole remains a privileged scaffold as a broad array of medicinally active agents encompass this heterocycle as a core nucleus. Pyrazole is a five-membered, aromatic ring containing two nitrogen atoms at adjacent positions that are readily able to show interactions with numerous receptor(s) and enzymes located on the target cells in the biological system. Pyrazole-containing compounds are acknowledged with anticyclooxygenases (anti-inflammatory), carbonic anhydrase inhibitor, α- glycosidase inhibitor, cholinesterase enzymes inhibitor, and anti-DNA gyrases activities. Noticeably, rimonabant, phenylbutazone, fipronil, difenamizole, celecoxib, antipyrine, fezolamide, and betazole are a few representatives of pyrazole-containing drugs. Objectives: The manuscript aims to review the detailed synthetic approaches applied to the synthesis of pyrazole derivatives. In particular, we examine recent scientific findings on antimicrobial, anti-tubercular, antiviral, anticancer, and anti-inflammatory perspectives of pyrazolecontaining analogues. Methods: Pyrazole analogues have been widely explored by the scientific community as many papers have been published in this regard. Numerous pyrazole-containing analogues have been designed, synthesized, and screened for their in vitro and in vivo bio-efficacy, and many of them are endowed with commendable pharmacological activities. Pyrazole analogues with improved antiviral, anticancer, and anti-inflammatory efficacy have also been well documented in patents granted to this heterocyclic nucleus. Results: This review outlines the recent advances in medicinal chemistry of pyrazole analogues with a special emphasis on structure-activity relationships to afford ideas for rational drug design and discovery and their impact on desired pharmacological applications. Conclusion: The information provided in this manuscript may help medicinal chemists to generate robust pyrazole analogues with high efficacy.

Background: Herbs are the primary feedstock for treating numerous infectious diseases occurring in humans. The herb serves as a potential resource for managing dental disorders by maintaining oral hygiene and reducing the growth of microbes through the use of antimicrobial agents. The body-to-mouth connection helps essential facets that reduce the vulnerability of inflammation and infections in the mouth. The herbal product offers a better alternative for oral care than antibiotics due to reduced side effects and increased patient compliance. Herbs used in dentistry contain antimicrobial, antiseptic, anti-bacterial, anti-fungal, and antiviral properties that help in reducing irritation, infections, and pain in the oral cavity. The resistance to antibiotics and overcoming their untoward side effects promoted the usage of herbals in dentistry. In addition, due to the affordability issues of allopathic medicines in rural areas, the dependency of poor people on herbal medicines has gained significant popularity in the Indian subcontinent. Objective: Oral disorders would be a significant health setback for humankind due to their severity if they remained untreated. This review promotes the efforts made to overcome the side effects of allopathic medicines and provide cost-effective herbal treatment for oral care. Oral disorders cause various infections like tooth decay, dental caries, gingivitis, fungal, viral and bacterial infections, plaque formation, pemphigus vulgaris, pyorrhoea and mouth ulcers. The use of herbal extracts of tulsi, neem, and turmeric as a natural healer and the safest antimicrobial provides better dental care treatment. In addition, aromatic agents like tulsi, neem, mint, clove, ginger, and turmeric as dental products have increased palatability for patients who have lost their taste buds with growing age and diseases. Methods: The literature search was conducted through academics, Google scholar, PubMed, WHO, and Sci.org using keywords dentistry, antimicrobials, herbs for dental management, experimental findings, bacterial strains, oral health, and hygiene. Results: The beneficial results of using various antimicrobial-containing herbs are gaining popularity throughout the world. Subsequently, it has been further suggested that antimicrobials and herbal extracts maintain oral hygiene, reduce bacterial lichens and biofilm adhesion, help in the management of oral infections, and improve health. Conclusion: Screening of newer antimicrobial formulations like dentifrices, gargles, throat paints, mouthwashes, and mouth sprays containing cost-effective herbals for promoting healthcare plays a pivotal role in developing herbal industries for dental care.

Background: Due to arising threats of microbial infectious diseases in the human population and the development of resistance against therapeutics, novel medicinal agents are required to counteract antimicrobial resistance. Heterocyclic rings, such as indole or pyrrole, have been acknowledged to possess various biological properties, like antimicrobial, anticancer, antiviral, antitubercular, etc., and metals, such as platinum, vanadium, zinc, selenium, etc., also show therapeutic actions. Thus, this work focuses on turning a heterocyclic ring compound (isatin) and metal (zinc) into a drug having antimicrobial potential. Objective: The objective of the study was to synthesize zinc complexes of isatin Schiff bases and evaluate their antibacterial and antifungal activity. Methods: Herein, the conventional method was used for the synthesis of isatin Schiff bases from isatin and different monosubstituted amines. Then, zinc complexes were prepared by using isatin Schiff bases and zinc acetate. Physicochemical characteristics, such as Rf value and melting point, were determined by TLC and decibel melting point apparatus, respectively. All the complexes were characterized by FT-IR and 1H NMR techniques. Further, the final zinc complexes were screened for antimicrobial potential by the serial dilution method. Some computational studies were also done with the help of MOPAC 2016. Results: In the present work, 14 complexes of zinc were obtained in harmonious yield from isatin Schiff bases using zinc acetate. Amongst the studied complexes, Z-3, Z-4, and Z-12 depicted maximum antimicrobial activity. Conclusion: 14 complexes of zinc were prepared by using 14 isatin Schiff bases, which were, in turn, prepared by isatin and different mono-substituted amines. Characterization of these complexes was done by using FT-IR and 1H NMR. All prepared metal complexes were obtained in appropriate yield. The synthesized complexes were screened for their antimicrobial potential.

Background: In India, several types of plants have been researched for the treatment of various ailments. Wedelia species, belonging to the Asteraceae family, is one of the wonder plants that has been utilised in Unani, Ayurvedic, and Homeopathic treatment for a long time. Objective: The components of Wedelia species were investigated in order to create novel powerful anti-fungal drugs with low toxicity and high efficacy followed by high bioavailability. Methods: Molergo Virtual Docker was used to test the chemical components of the plant for antifungal potential against the enzyme 14-demethylase. Results: According to the findings, about fifteen compounds were identified as promising compounds with a high dock score and number of interactions. Conclusion: These compounds can further be isolated and worked upon for future research.

Background: COVID-19 viral infection is a worldwide pandemic that created a major concern regarding the need for a suitable drug candidate for viral infections. The entire scientific community is putting up their efforts and research to find a proper cure for this. The traditional Indian Siddha system of medicine is one of the oldest forms of medicine, which includes medicine, Varma, alchemy, yoga, and rejuvenation. Methods: Kabasura kudineer is one of the Siddha herbal preparations that are being recommended by the State government of Tamilnadu, India, for protection against COVID-19. It is recommended due to its claims to have anti-viral properties and other numerous health benefits. Results: This article thoroughly examines the Kabasura kudineer, a polyherbal formulation comprising 15 powerful ancient Indian herbals that possess various potential phytochemicals providing numerous therapeutic activities. Also, the review highlights the most important therapeutic benefits of this formulation like anti-viral properties along with other activities such as immunomodulatory, bronchodilatory, anti-asthmatic, etc., Conclusion: The role of Kabasura kudineer against viral diseases, especially the recent COVID- 19, is tremendous, and there is a need to enhance further research on this powerful formulation to make it more efficient and useful to the entire people community.

Background: Field-based 3D-QSAR, homology modelling, molecular docking, and ADMET studies have been carried out to determine the binding mode and drug likeliness profile of imidazo[1,2- a]pyridine derivatives as anti-tubercular agents. Objective: The objective of this study is to design new anti-tubercular agents using field-based 3D-QSAR and molecular docking approaches and to ascertain the binding manner and drug-likeliness profile of imidazo[1,2-a]pyridine derivatives as antitubercular agents on ATP synthase protein. Methods: A statistically significant 3D-QSAR model was generated with the dataset of 30 active agonists on ATP synthase whose pIC50 values ranged from 4.0 μM to 8.30 μM. The same dataset was analysed for ADME-T properties and docked to the homology modeled ATP synthase protein. Moreover, information from3D-QSAR contour maps was used in designing new molecules. Results: The constructed 3D-QSAR model had a high correlation coefficient (R2=0.9688) and crossvalidation coefficient (Q2=0.9045), and F value (176) at the 3 component PLS factor. The homology modeled protein ‘ac9’ was validated with various parameters like Ramachandran plot (92.5 %), ERRAT plot (98.43 %), and ProSA (-1.78 chain ‘C’; -2.74 chain ‘A’). The protein was also examined for physicochemical properties, which showed the acidic and hydrophobic nature of the protein. The docking score of dataset compound no. PF19 (-9.97 Kcal/mol) was found to be almost similar to that of bedaquiline (- 10.08 Kcal/mol). Based on previous results from 3D-QSAR modelling and molecular docking, four new molecules were designed. The newly designed molecules (M1-M4) were docked; amongst them, M3(- 9.82 Kcal/mol) scored the highest. They were further analysed for drug-likeliness, ADME-T, and synthetic assessability. The findings suggested that these compounds had a strong possibility of becoming ATP-synthase inhibitors. Conclusion: The various in silico approaches used in the present study offer new avenues for designing novel molecules against ATP synthase from M. tuberculosis and can be employed for the drug discovery programme.

Background: Fusarium species are significant plant and human pathogens. Current chemical agents against them are limited by their side effects and developed resistance, requiring an alternative way to overcome this problem. Objective: We aimed to assess the inhibitory effects of Streptomyces strains isolated from soil samples against Fusarium species. Methods: Totally 250 samples were collected. Morphological and physiological characterizations of the isolates were investigated. All isolates were evaluated to test their antifungal activity against Fusarium oxysporum and Fusarium solani. Molecular identification of active Streptomyces isolates was conducted using the 16S rRNA gene. Results: Fifty Streptomyces isolates were obtained. Among them, two strains showed the most antagonistic effect against Fusarium species. According to the analysis of 16S rRNA gene sequences, these isolates were identified as Streptomyces rochei. Conclusion: The obtained results of this study indicated that S. rochei could use as a potent source of bioactive compounds with antifungal activity.

Background: Chronic non-communicable diseases were interlinked with inflammation, and infections should respond to the core of major diseases in both acute and chronic conditions. In drug discovery, developing a drug that acts as an anti-infective agent (anti-microbial and antiinflammatory) must be ideal and challenging for managing many chronic diseases. Objective: In this study, six lead pyrazoline hybrids were synthesized by cyclization of chalcones and characterized by various spectroscopic and elemental analyses. All synthesized compounds were screened for anti-inflammatory and anti-microbial activity by computational tools and biological evaluation. Methods: Synthesized pyrazoline analogues were characterized by various spectroscopic techniques and evaluated for prediction of pharmacokinetics, physicochemical properties and Molecular docking studies of various targeted enzymes on microbial and inflammatory mediators. Those compounds were screened by anti-microbial and anti-inflammatory activities by several in-vitro and in-vivo methods. Results: The synthesized compounds (A1-A6) were screened for anti-inflammatory activity in which compound A2 produced effective percentage inhibition (45.8 %) potent activity compared with that of standard indomethacin (49.7 %) in the carrageenan paw edema method were observed. The anti-microbial activity was screened on synthesized compounds, among which A3 [2-(1,3- diphenyl-4,5-dihydro-1H-pyrazol-5-yl) phenol, A2 [5-(4-chlorophenyl)-1,3-diphenyl-4,5-dihydro- 1H-pyrazole] produced potential percentage zone of inhibition between 80 - 70 % for bacterial strains and 94 - 89 % for fungal strains were observed. The minimum inhibitory concentration values of those compounds were 1.56 to 6.25 μg/ml for bacterial strains, and 1.56 to 12.5 μg/ml for fungal strains were noted compared with the standard gatifloxacin and clotrimazole, respectively. The molecular docking, pharmacokinetics and toxicity predictions on those compounds were supported further for developing potent anti-infective agents. Conclusion: The hypothesis of this research was correlated with the results of anti-inflammatory and anti-microbial activity. The binding interactions of respective enzymes coincided with a reduction of paw edema in the anti-inflammatory model and a zone of inhibition in anti-microbial activity.

Background: In herbal medicine, Centaurea is used in the treatment of many diseases such as dizziness, headaches, etc. It also reduces inflammatory pain and is used to treat liver diseases. The roots of Centaurea acaulis and Centaurea pullata have not yet been studied for biological properties. Objective: The aim of this research was to evaluate the chemical composition and the antiinflammatory, antioxidant and neuroprotective properties of hexane extracts of Centaurea acaulis and Centaurea pullata roots, and their major component, aplotaxene. Methods: The hexane extract was prepared by the maceration process and identified by GC and GCMS. Aplotaxene was isolated by flash chromatography. The antioxidant activity was assessed using 2,2- diphenyl 1-picrylhydrazyle DPPH, the β-carotene bleaching, and Ferric Reducing Antioxidant Power (FRAP) methods. The anti-inflammatory effect was assessed by egg albumin denaturation assay and the neuroprotective activity was assessed against acetyl cholinesterase (AChE) and Butyrylcholinesterase (BChE). Results: The chemical composition of hexane extract of Centaurea pullata was mainly represented by non-terpenic compounds such as Aplotaxene (80.3%), while, hexane extract of Centaurea acaulis was characterized by high levels of Aplotaxene (56.9%), 9-oxabicyclo(6,1,0)nonane (9.2%), Caryophyllene oxide (8.3%) and Isocaryophyllene (6.0%). The hexane extracts of the two Centaurea showed very good antioxidant activities with all three methods. Aplotaxene has shown excellent antioxidant activity compared to Butylated hydroxytoluene (BHT) and ascorbic acid. Centaurea acaulis hexane extract showed very high anti-inflammatory activity with an IC50 of 0.76 mg/L in the egg albumin denaturation test compared to diclofenac (IC50 of 1.01 mg/L). The extract of Centaurea pullata and Aplotaxene showed an interesting anti-inflammatory activity with IC50s of 1.72 and 1.36 mg/L, but which remains lower than that of diclofenac sodium. The neuroprotective activity of Centurea pullata and Centaurea acaulis extracts, and Aplotaxene did not show inhibition against AChE, whereas they inhibited BChE with IC50 values of 92.3, 583, and 81.5 mg/L, respectively. Conclusion: Further analysis is still needed to further demonstrate the biological efficacy of Centaurea acaulis and Centaurea pullata extracts and Aplotaxene.

Background: In the past few decades, mankind has been suffering from tormented life-threatening infectious diseases caused by multidrug-resistant bacteria. As a result, new antimicrobial classes with distinct modes of action are required to combat multidrug-resistant infections. Objective: The pyrazole-based pyrimidine and pyrazolone motifs were synthesized, characterized, and screened for their antimicrobial activity. Molecular docking was carried out for the development of antimicrobial agents based on the results of biological activity obtained. Methods: We have synthesized a new series of pyrazole containing pyrimidine-pyrazolone hybrids by using multi-step reactions in the search for antimicrobial agents (7a-o). The structures were determined by ¹H NMR, ¹³C NMR, IR, and mass spectroscopy techniques. Moreover, synthesized compounds were evaluated for their antimicrobial activity by using the serial Broth dilution method. Results: Antimicrobial activity of synthesized compounds has been tested against bacterial and fungal strains. Compound 7o was most effective against S. aureus with MIC = 0.096 M/mL. A molecular docking study against microbial DNA gyrase revealed important information about the mechanisms underlying antimicrobial efficacy. Through significant interactions with active site residues, all of the compounds were able to dock well into the enzyme's active site. Furthermore, compounds 7a (0.531 M/mL), 7b (0.456 M/mL), and 7m (0.485 M/mL) showed excellent antifungal activity against C. albicans compared to the positive control griseofulvin. Conclusion: It has been concluded that compounds containing electron-donating groups are found to be most active against bacterial strains, while compounds having both electron-donating as well as electron-withdrawing groups are most favorable for antifungal activity.

Background: Immunological CD4+ T cell gain is representative of an effective response to combined antiretroviral therapy (cART) in HIV-infected persons. Nevertheless, baseline clinical and socio-demographic factors are significant moderators of this response. Objective: This study investigates the impact of viral suppression on immune reconstitution and body mass index (BMI) following ART initiation in Zaria, a resource-poor subpopulation in Northwestern Nigeria. Methods: A hospital-based prospective study was conducted among 44 cART-naïve HIVpositive individuals. BMI, CD4 counts, and viral load were measured using standard methods at baseline and six months after initiation of cART. Results: There was no significant difference in the CD4+ T-cell count at baseline and 6 months on cART along with the different categories (C: < 200 cells/mm3, B: 200-499 cell/mm3, A: >500 cell/mm3). However, ~90% of subjects in category C had immunological failure 6 months on cART. The number of subjects with viral copies < 1000/ml at baseline was 7(16%), while at 6 months on cART, the number increased to 35(80%), P<0.05. Viral suppression (VL copies <1000/ml) was significantly correlated with immune recovery (CD4 count > 200 cell/mm3) in obese individuals (P<0.02). There was a significant association between subjects with CD4+ count < 200 cells/mm3 after 6 months on ART and having baseline VL copies of <1000/ml and low BMI (aOR 2.2 and 2.4 respectively, p≤0.05). Conclusion: Findings from this study suggest a high prevalence of paradoxical VL suppression but not immune CD4 gain in the studied subjects following cART. Larger studies are needed to corroborate these findings.

Kelulut and Yemeni Sidr honey has been documented to have various therapeutic properties. Investigations associated with the medicinal properties and physicochemical characteristics of Kelulut and Yemeni Sidr honey are growing broadly and receiving raised awareness. This study incorporated and analysed the findings on the biological and physicochemical properties of Kelulut and Yemeni Sidr honey. Kelulut and Yemeni Sidr honey was found to have a wide variety of biological effects attributed to their physicochemical characteristics. Findings showed that Kelulut and Yemeni Sidr honey have anti-bacterial, antibiofilm, anti-virulence, anti-oxidative, anti-cancer, anti-inflammatory, anti-diabetic, antiobesity and wound-healing properties. The physicochemical properties of Kelulut and Yemeni Sidr honey were compared and discussed and results revealed that they have high-quality contents and excellent antioxidant sources.