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20 pages, 32255 KiB

Open AccessArticle

Facile One-Pot Multicomponent Synthesis of Pyrazolo-Thiazole Substituted Pyridines with Potential Anti-Proliferative Activity: Synthesis, In Vitro and In Silico Studies

by Islam H. El Azab, Rania B. Bakr and Nadia A. A. Elkanzi

Molecules 2021, 26(11), 3103; https://doi.org/10.3390/molecules26113103 - 22 May 2021

Cited by 22 | Viewed by 2877

Abstract

Pyrazolothiazole-substituted pyridine conjugates are an important class of heterocyclic compounds with an extensive variety of potential applications in the medicinal and pharmacological arenas. Therefore, herein, we describe an efficient and facile approach for the synthesis of novel pyrazolo-thiazolo-pyridine conjugate 4, via multicomponent [...] Read more.

Pyrazolothiazole-substituted pyridine conjugates are an important class of heterocyclic compounds with an extensive variety of potential applications in the medicinal and pharmacological arenas. Therefore, herein, we describe an efficient and facile approach for the synthesis of novel pyrazolo-thiazolo-pyridine conjugate 4, via multicomponent condensation. The latter compound was utilized as a base for the synthesis of two series of 15 novel pyrazolothiazole-based pyridine conjugates (5–16). The newly synthesized compounds were fully characterized using several spectroscopic methods (IR, NMR and MS) and elemental analyses. The anti-proliferative impact of the new synthesized compounds 5–13 and 16 was in vitro appraised towards three human cancer cell lines: human cervix (HeLa), human lung (NCI-H460) and human prostate (PC-3). Our outcomes regarding the anti-proliferative activities disclosed that all the tested compounds exhibited cytotoxic potential towards all the tested cell lines with IC₅₀ = 17.50–61.05 µM, especially the naphthyridine derivative 7, which exhibited the most cytotoxic potential towards the tested cell lines (IC₅₀ = 14.62–17.50 µM) compared with the etoposide (IC50 = 13.34–17.15 µM). Moreover, an in silico docking simulation study was performed on the newly prepared compounds within topoisomerase II (3QX3), to suggest the binding mode of these compounds as anticancer candidates. The in silico docking results indicate that compound 7 was a promising lead anticancer compound which possesses high binding affinity toward topoisomerase II (3QX3) protein. Full article

(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds II)

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10 pages, 3337 KiB

Open AccessArticle

Synthesis and Evaluation of Chalcone Derivatives as Novel Sunscreen Agent

by Lucia Wiwid Wijayanti, Respati Tri Swasono, Wonkoo Lee and Jumina Jumina

Molecules 2021, 26(9), 2698; https://doi.org/10.3390/molecules26092698 - 4 May 2021

Cited by 29 | Viewed by 5439

Abstract

Ultraviolet (UV) irradiation is a serious problem for skin health thus the interest in the research to develop sunscreen agent has been increasing. Chalcone is a promising compound to be developed as its chromophore absorbs in the UV region. Therefore, in the present [...] Read more.

Ultraviolet (UV) irradiation is a serious problem for skin health thus the interest in the research to develop sunscreen agent has been increasing. Chalcone is a promising compound to be developed as its chromophore absorbs in the UV region. Therefore, in the present work, we synthesized eight chalcone derivatives through Claisen–Schmidt condensation at room temperature. The evaluation of the optical properties of each chalcone derivatives in the UV region was conducted through spectroscopic and computational studies. The synthesized chalcones were obtained in good yields and they were active in the UV region. The results revealed that more methoxy substituents to chalcone leads toward red shift. All chalcone derivatives have high molar absorptivity value (21,000–56,000) demonstrating that they have the potential to be used as the sunscreen agent. The cytotoxicity assay showed that chalcone derivatives were demonstrating low toxicity toward normal human fibroblast cell, which is remarkable. Therefore, we concluded that the synthesized chalcones in this work were potential to be developed as novel sunscreen agents in real application. Full article

(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds II)

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16 pages, 2175 KiB

Open AccessArticle

Synthesis, Antifungal Activity, and 3D-QSAR Study of Novel Nopol-Derived 1,3,4-Thiadiazole-Thiourea Compounds

by Ming Chen, Wen-Gui Duan, Gui-Shan Lin, Zhong-Tian Fan and Xiu Wang

Molecules 2021, 26(6), 1708; https://doi.org/10.3390/molecules26061708 - 18 Mar 2021

Cited by 23 | Viewed by 3726

Abstract

A series of novel nopol derivatives bearing the 1,3,4-thiadiazole-thiourea moiety were designed and synthesized by multi-step reactions in search of potent natural product-based antifungal agents. Their structures were confirmed by FT-IR, NMR, ESI-MS, and elemental analysis. Antifungal activity of the target compounds was [...] Read more.

A series of novel nopol derivatives bearing the 1,3,4-thiadiazole-thiourea moiety were designed and synthesized by multi-step reactions in search of potent natural product-based antifungal agents. Their structures were confirmed by FT-IR, NMR, ESI-MS, and elemental analysis. Antifungal activity of the target compounds was preliminarily evaluated by in vitro methods against Fusarium oxysporum f. sp. cucumerinum, Cercospora arachidicola, Physalospora piricola, Alternaria solani, Gibberella zeae, Rhizoeotnia solani, Bipolaris maydis, and Colleterichum orbicalare at 50 µg/mL. All the target compounds exhibited better antifungal activity against P. piricola, C. arachidicola, and A. solani. Compound 6j (R = m, p-Cl Ph) showed the best broad-spectrum antifungal activity against all the tested fungi. Compounds 6c (R = m-Me Ph), 6q (R = i-Pr), and 6i (R = p-Cl Ph) had inhibition rates of 86.1%, 86.1%, and 80.2%, respectively, against P. piricola, much better than that of the positive control chlorothalonil. Moreover, compounds 6h (R = m-Cl Ph) and 6n (R = o-CF₃ Ph) held inhibition rates of 80.6% and 79.0% against C. arachidicola and G. zeae, respectively, much better than that of the commercial fungicide chlorothalonil. In order to design more effective antifungal compounds against A. solani, analysis of the three-dimensional quantitative structure–activity relationship (3D-QSAR) was carried out using the CoMFA method, and a reasonable and effective 3D-QSAR model (r² = 0.992, q² = 0.753) has been established. Furthermore, some intriguing structure–activity relationships were found and are discussed by theoretical calculation. Full article

(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds II)

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14 pages, 1815 KiB

Open AccessArticle

Studies on the Enantioselective Synthesis of E-Ethylidene-bearing Spiro[indolizidine-1,3′-oxindole] Alkaloids

by Nihan Yayik, Maria Pérez, Elies Molins, Joan Bosch and Mercedes Amat

Molecules 2021, 26(2), 428; https://doi.org/10.3390/molecules26020428 - 15 Jan 2021

Viewed by 3111

Abstract

A synthetic route for the enantioselective construction of the tetracyclic spiro[indolizidine-1,3′-oxindole] framework present in a large number of oxindole alkaloids, with a cis H-3/H-15 stereochemistry, a functionalized two-carbon substituent at C-15, and an E-ethylidene substituent at C-20, is reported. The key steps [...] Read more.

A synthetic route for the enantioselective construction of the tetracyclic spiro[indolizidine-1,3′-oxindole] framework present in a large number of oxindole alkaloids, with a cis H-3/H-15 stereochemistry, a functionalized two-carbon substituent at C-15, and an E-ethylidene substituent at C-20, is reported. The key steps of the synthesis are the generation of the tetracyclic spirooxindole ring system by stereoselective spirocyclization from a tryptophanol-derived oxazolopiperidone lactam, the removal of the hydroxymethyl group, and the stereoselective introduction of the E-ethylidene substituent by acetylation at the α-position of the lactam carbonyl, followed by hydride reduction and elimination. Following this route, the 21-oxo derivative of the enantiomer of the alkaloid 7(S)-geissoschizol oxindole has been prepared. Full article

(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds II)

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Review

Jump to: Research

40 pages, 8780 KiB

Open AccessReview

Metabolic N-Dealkylation and N-Oxidation as Elucidators of the Role of Alkylamino Moieties in Drugs Acting at Various Receptors

by Babiker M. EH-Haj

Molecules 2021, 26(7), 1917; https://doi.org/10.3390/molecules26071917 - 29 Mar 2021

Cited by 17 | Viewed by 10897

Abstract

Metabolic reactions that occur at alkylamino moieties may provide insight into the roles of these moieties when they are parts of drug molecules that act at different receptors. N-dealkylation of N,N-dialkylamino moieties has been associated with retaining, attenuation or [...] Read more.

Metabolic reactions that occur at alkylamino moieties may provide insight into the roles of these moieties when they are parts of drug molecules that act at different receptors. N-dealkylation of N,N-dialkylamino moieties has been associated with retaining, attenuation or loss of pharmacologic activities of metabolites compared to their parent drugs. Further, N-dealkylation has resulted in clinically used drugs, activation of prodrugs, change of receptor selectivity, and providing potential for developing fully-fledged drugs. While both secondary and tertiary alkylamino moieties (open chain aliphatic or heterocyclic) are metabolized by CYP450 isozymes oxidative N-dealkylation, only tertiary alkylamino moieties are subject to metabolic N-oxidation by Flavin-containing monooxygenase (FMO) to give N-oxide products. In this review, two aspects will be examined after surveying the metabolism of representative alkylamino-moieties-containing drugs that act at various receptors (i) the pharmacologic activities and relevant physicochemical properties (basicity and polarity) of the metabolites with respect to their parent drugs and (ii) the role of alkylamino moieties on the molecular docking of drugs in receptors. Such information is illuminative in structure-based drug design considering that fully-fledged metabolite drugs and metabolite prodrugs have been, respectively, developed from N-desalkyl and N-oxide metabolites. Full article

(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds II)

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16 pages, 4230 KiB

Open AccessReview

Chemical Strategies towards the Synthesis of Betulinic Acid and Its More Potent Antiprotozoal Analogues

by André Barreto Cunha, Ronan Batista, María Ángeles Castro and Jorge Mauricio David

Molecules 2021, 26(4), 1081; https://doi.org/10.3390/molecules26041081 - 18 Feb 2021

Cited by 16 | Viewed by 3998

Abstract

Betulinic acid (BA, 3β-hydroxy-lup-20(29)-en-28-oic acid) is a pentacyclic triterpene acid present predominantly in Betula ssp. (Betulaceae) and is also widely spread in many species belonging to different plant families. BA presents a wide spectrum of remarkable pharmacological properties, such as cytotoxic, anti-HIV, anti-inflammatory, [...] Read more.

Betulinic acid (BA, 3β-hydroxy-lup-20(29)-en-28-oic acid) is a pentacyclic triterpene acid present predominantly in Betula ssp. (Betulaceae) and is also widely spread in many species belonging to different plant families. BA presents a wide spectrum of remarkable pharmacological properties, such as cytotoxic, anti-HIV, anti-inflammatory, antidiabetic and antimicrobial activities, including antiprotozoal effects. The present review first describes the sources of BA and discusses the chemical strategies to produce this molecule starting from betulin, its natural precursor. Next, the antiprotozoal properties of BA are briefly discussed and the chemical strategies for the synthesis of analogues displaying antiplasmodial, antileishmanial and antitrypanosomal activities are systematically presented. The antiplasmodial activity described for BA was moderate, nevertheless, some C-3 position acylated analogues showed an improvement of this activity and the hybrid models—with artesunic acid—showed the most interesting properties. Some analogues also presented more intense antileishmanial activities compared with BA, and, in addition to these, heterocycles fused to C-2/C-3 positions and amide derivatives were the most promising analogues. Regarding the antitrypanosomal activity, some interesting antitrypanosomal derivatives were prepared by amide formation at the C-28 carboxylic group of the lupane skeleton. Considering that BA can be produced either by isolation of different plant extracts or by chemical transformation of betulin, easily obtained from Betula ssp., it could be said that BA is a molecule of great interest as a starting material for the synthesis of novel antiprotozoal agents. Full article

(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds II)

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21 pages, 347 KiB

Open AccessReview

Azadirachta indica A. Juss. In Vivo Toxicity—An Updated Review

by Teresa M. Braga, Lídia Rocha, Tsz Yan Chung, Rita F. Oliveira, Cláudia Pinho, Ana I. Oliveira, Joaquim Morgado and Agostinho Cruz

Molecules 2021, 26(2), 252; https://doi.org/10.3390/molecules26020252 - 6 Jan 2021

Cited by 31 | Viewed by 5647

Abstract

The Neem tree, Azadirachta indica A. Juss., is known for its large spectrum of compounds with biological and pharmacological interest. These include, among others, activities that are anticancer, antibacterial, antiviral, and anti-inflammatory. Some neem compounds are also used as insecticides, herbicides, and/or antifeedants. [...] Read more.

The Neem tree, Azadirachta indica A. Juss., is known for its large spectrum of compounds with biological and pharmacological interest. These include, among others, activities that are anticancer, antibacterial, antiviral, and anti-inflammatory. Some neem compounds are also used as insecticides, herbicides, and/or antifeedants. The safety of these compounds is not always taken into consideration and few in vivo toxicity studies have been performed. The current study is a literature review of the latest in vivo toxicity of A. indica. It is divided in two major sections—aquatic animals toxicity and mammalian toxicity—each related to neem’s application as a pesticide or a potential new therapeutic drug, respectively. Full article

(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds II)

19 pages, 2627 KiB

Open AccessReview

From Target-Oriented to Motif-Oriented: A Case Study on Nannocystin Total Synthesis

by Weicheng Zhang

Molecules 2020, 25(22), 5327; https://doi.org/10.3390/molecules25225327 - 15 Nov 2020

Cited by 9 | Viewed by 2689

Abstract

Natural product total synthesis is in essence target-oriented in that a set of organic transformations are orchestrated into a workable process, leading ultimately to the target molecule with a predefined architecture. For a bioactive lead, proof of synthetic viability is merely the beginning. [...] Read more.

Natural product total synthesis is in essence target-oriented in that a set of organic transformations are orchestrated into a workable process, leading ultimately to the target molecule with a predefined architecture. For a bioactive lead, proof of synthetic viability is merely the beginning. Ensuing effort repurposes the initial synthesis for structural diversification in order to probe structure-activity relationship (SAR). Yet accessibility is not equal to flexibility; moving from convergency to divergency, it is not always feasible to explore the chemical space around a particular substructure of interest simply by tweaking an established route. In this situation, the motif-oriented strategy becomes a superior choice, which gives priority to synthetic flexibility at the concerned site such that a route is adopted only if it is capable of implementing diversification therein. This strategy was recently devised by Fürstner et al., enabling them to achieve total synthesis of both natural and non-natural nannocystins varied at an otherwise challenging position. The present review examines seven distinctive nannocystin total syntheses reported thus far and showcases the merits of conventional (target-oriented) as well as motif-oriented strategies, concluding that these two approaches complement each other and are both indispensable for natural product based drug discovery. Full article

(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds II)

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19 pages, 3106 KiB

Open AccessReview

Antibacterial Natural Halimanes: Potential Source of Novel Antibiofilm Agents

by Ignacio E. Tobal, Alejandro M. Roncero, Rosalina F. Moro, David Díez and Isidro S. Marcos

Molecules 2020, 25(7), 1707; https://doi.org/10.3390/molecules25071707 - 8 Apr 2020

Cited by 3 | Viewed by 2995

Abstract

The development of new agents against bacteria is an urgent necessity for human beings. The structured colony of bacterial cells, called the biofilm, is used to defend themselves from biocide attacks. For this reason, it is necessary to know their structures, develop new [...] Read more.

The development of new agents against bacteria is an urgent necessity for human beings. The structured colony of bacterial cells, called the biofilm, is used to defend themselves from biocide attacks. For this reason, it is necessary to know their structures, develop new agents to eliminate them and to develop new procedures that allow an early diagnosis, by using biomarkers. Among natural products, some derivatives of diterpenes with halimane skeleton show antibacterial activity. Some halimanes have been isolated from marine organisms, structurally related with halimanes isolated from Mycobacterium tuberculosis. These halimanes are being evaluated as virulence factors and as tuberculosis biomarkers, this disease being one of the major causes of mortality and morbidity. In this work, the antibacterial halimanes will be reviewed, with their structural characteristics, activities, sources and the synthesis known until now. Full article

(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds II)

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