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Synthesis of symmetrical bis-Schiff base-disulfide hybrids as highly effective anti-leishmanial agents

Taha M, Sain AA, Ali M, Anouar EH, Rahim F, Ismail NH, et al.

Bioorg Chem, 2020 06;99:103819.
PMID: 32325334 DOI: 10.1016/j.bioorg.2020.103819

Leishmaniasis has affected a wider part of population around the globe. Most often, the existing regiments to battle against leishmaniasis are inadequate and limited. In our ongoing efforts to develop new leishmanicidal agents, we have synthesized a series of novel and symmetrical bis-Schiff base-disulfide hybrids 1-27. Intermediate disulfide was synthesized from corresponding 2-aminothiol followed by reacting the coupled adduct with various aromatic aldehydes. All these compounds showed outstanding inhibition when compared with standard (Table 1). Out of twenty seven analogues, twenty two analogues i.e. 1-5, 7-13, 17-21, 23-27 analogues showed excellent inhibitory potential with EC50 values ranging from 0.010 ± 0.00 to 0.096 ± 0.01 μM while five compounds i.e. 6, 14-16, and 22 showed good inhibitory potential with EC50 values ranging from 0.10 ± 0.00 to 0.137 ± 0.01 μM when compared with the standard Amphotericin B. Structure-activity relationship has been established while molecular docking studies were performed to pin the binding interaction of active molecules. This study will help to develop new antileishmanial lead compounds.

Matched MeSH terms: Antiprotozoal Agents/chemical synthesis
Synthesis and antileishmanial activity of fluorinated rhodacyanine analogues: The 'fluorine-walk' analysis

Lasing T, Phumee A, Siriyasatien P, Chitchak K, Vanalabhpatana P, Mak KK, et al.

Bioorg Med Chem, 2020 01 01;28(1):115187.
PMID: 31761725 DOI: 10.1016/j.bmc.2019.115187

In a search for potent antileishmanial drug candidates, eighteen rhodacyanine analogues bearing fluorine or perfluoroalkyl substituents at various positions were synthesized. These compounds were tested for their inhibitory activities against Leishmania martiniquensis and L. orientalis. This 'fluorine-walk' analysis revealed that the introduction of fluorine atom at C-5, 6, 5', or 6' on the benzothiazole units led to significant enhancement of the activity, correlating with the less negative reduction potentials of the fluorinated analogues confirmed by the electrochemical study. On the other hand, CF3 and OCF3 groups were found to have detrimental effects, which agreed with the poor aqueous solubility predicted by the in silico ADMET analysis. In addition, some of the analogues including the difluorinated species showed exceptional potency against the promastigote and axenic amastigote stages (IC50 = 40-85 nM), with the activities surpassing both amphotericin B and miltefosine.

Matched MeSH terms: Antiprotozoal Agents/chemical synthesis
Synthesis of 2-methoxybenzoylhydrazone and evaluation of their antileishmanial activity

Taha M, Baharudin MS, Ismail NH, Khan KM, Jaafar FM, Samreen, et al.

Bioorg Med Chem Lett, 2013 Jun 1;23(11):3463-6.
PMID: 23608761 DOI: 10.1016/j.bmcl.2013.03.051

Compounds 1-25 showed varying degree of antileishmanial activities with IC50 values ranging between 1.95 and 88.56 μM. Compounds 2, 10, and 11 (IC50=3.29±0.07 μM, 1.95±0.04 μM, and 2.49±0.03 μM, respectively) were found to be more active than standard pentamidine (IC50=5.09±0.04 μM). Compounds 7 (IC50=7.64±0.1 μM), 8 (IC50=13.17±0.46 μM), 18 (IC50=13.15±0.02 μM), and 24 (IC50=15.65±0.41 μM) exhibited good activities. Compounds 1, 3, 4, 5, 9, 12, 15, 18, and 19 were found to be moderately active. Compounds 13, 14, 16, 17, 20-25 showed weak activities with IC50 values ranging between 57 and 88 μM.

Matched MeSH terms: Antiprotozoal Agents/chemical synthesis*
Synthesis of novel derivatives of 4-methylbenzimidazole and evaluation of their biological activities

Taha M, Ismail NH, Jamil W, Rashwan H, Kashif SM, Sain AA, et al.

Eur J Med Chem, 2014 Sep 12;84:731-8.
PMID: 25069019 DOI: 10.1016/j.ejmech.2014.07.078

4-Methylbenzimidazole 1-28 novel derivatives were synthesized and evaluated for their antiglycation and antioxidant activities. Compounds 1-7 and 11 showed excellent activities ranged 140-280 μM, better than standard drug rutin (294.46 ± 1.50 μM). Compound 1-28 were also evaluated for DPPH activities. Compounds 1-8 showed excellent activities, ranging 12-29 μM, better than standard drug n-propylgallate (IC50 = 30.30 ± 0.40 μM). For superoxide anion scavenging activity, compounds 1-7 showed better activity than standard n-propylgallate (IC50 = 106.34 ± 1.6 μM), ranged 82-104 μM. These compounds were found to be nontoxic to THP-1 cells.

Matched MeSH terms: Antiprotozoal Agents/chemical synthesis*
Fulltext Anti-amoebic properties of carbonyl thiourea derivatives

Ibrahim MA, Yusof MS, Amin NM

Molecules, 2014 Apr 22;19(4):5191-204.
PMID: 24759076 DOI: 10.3390/molecules19045191

Thiourea derivatives display a broad spectrum of applications in chemistry, various industries, medicines and various other fields. Recently, different thiourea derivatives have been synthesized and explored for their anti-microbial properties. In this study, four carbonyl thiourea derivatives were synthesized and characterized, and then further tested for their anti-amoebic properties on two potential pathogenic species of Acanthamoeba, namely A. castellanii (CCAP 1501/2A) and A. polyphaga (CCAP 1501/3A). The results indicate that these newly-synthesized thiourea derivatives are active against both Acanthamoeba species. The IC50 values obtained were in the range of 2.39-8.77 µg·mL⁻¹ (9.47-30.46 µM) for A. castellanii and 3.74-9.30 µg·mL⁻¹ (14.84-31.91 µM) for A. polyphaga. Observations on the amoeba morphology indicated that the compounds caused the reduction of the amoeba size, shortening of their acanthopodia structures, and gave no distinct vacuolar and nuclear structures in the amoeba cells. Meanwhile, fluorescence microscopic observation using acridine orange and propidium iodide (AOPI) staining revealed that the synthesized compounds induced compromised-membrane in the amoeba cells. The results of this study proved that these new carbonyl thiourea derivatives, especially compounds M1 and M2 provide potent cytotoxic properties toward pathogenic Acanthamoeba to suggest that they can be developed as new anti-amoebic agents for the treatment of Acanthamoeba keratitis.

Matched MeSH terms: Antiprotozoal Agents/chemical synthesis
Synthetic Dihydropyridines as Novel Antiacanthamoebic Agents

Anwar A, Siddiqui R, Hameed A, Shah MR, Khan NA

Med Chem, 2020;16(7):841-847.
PMID: 31544702 DOI: 10.2174/1573406415666190722113412

BACKGROUND: Acanthamoeba is an opportunistic pathogen widely spread in the environment. Acanthamoeba causes excruciating keratitis which can lead to blindness. The lack of effective drugs and its ability to form highly resistant cyst are one of the foremost limitations against successful prognosis. Current treatment involves mixture of drugs at high doses but still recurrence of infection can occur due to ineffectiveness of drugs against the cyst form. Pyridine and its natural and synthetic derivatives are potential chemotherapeutic agents due to their diverse biological activities.
OBJECTIVE: To study the antiamoebic effects of four novel synthetic dihydropyridine (DHP) compounds against Acanthamoeba castellanii belonging to the T4 genotype. Furthermore, to evaluate their activity against amoeba-mediated host cells cytopathogenicity as well as their cytotoxicity against human cells.
METHODS: Dihydropyridines were synthesized by cyclic dimerization of alkylidene malononitrile derivatives. Four analogues of functionally diverse DHPs were tested against Acanthamoeba castellanii by using amoebicidal, encystation and excystation assays. Moreover, Lactate dehydrogenase assays were carried out to study cytopathogenicity and cytotoxicity against human cells.
RESULTS: These compounds showed significant amoebicidal and cysticidal effects at 50 μM concentration, whereas, two of the DHP derivatives also significantly reduced Acanthamoebamediated host cell cytotoxicity. Moreover, these DHPs were found to have low cytotoxicity against human cells suggesting a good safety profile.
CONCLUSION: The results suggest that DHPs have potential against Acanthamoeba especially against the more resistant cyst stage and can be assessed further for drug development.

Matched MeSH terms: Antiprotozoal Agents/chemical synthesis
Fulltext The Development of Drugs against Acanthamoeba Infections

Siddiqui R, Aqeel Y, Khan NA

Antimicrob Agents Chemother, 2016 11;60(11):6441-6450.
PMID: 27600042 DOI: 10.1128/AAC.00686-16

For the past several decades, there has been little improvement in the morbidity and mortality associated with Acanthamoeba keratitis and Acanthamoeba encephalitis, respectively. The discovery of a plethora of antiacanthamoebic compounds has not yielded effective marketed chemotherapeutics. The rate of development of novel antiacanthamoebic chemotherapies of translational value and the lack of interest of the pharmaceutical industry in developing such chemotherapies have been disappointing. On the other hand, the market for contact lenses/contact lens disinfectants is a multi-billion-dollar industry and has been successful and profitable. A better understanding of drugs, their targets, and mechanisms of action will facilitate the development of more-effective chemotherapies. Here, we review the progress toward phenotypic drug discovery, emphasizing the shortcomings of useable therapies.

Matched MeSH terms: Antiprotozoal Agents/chemical synthesis
Synthesis and molecular modelling studies of phenyl linked oxadiazole-phenylhydrazone hybrids as potent antileishmanial agents

Taha M, Ismail NH, Imran S, Anouar EH, Selvaraj M, Jamil W, et al.

Eur J Med Chem, 2017 Jan 27;126:1021-1033.
PMID: 28012342 DOI: 10.1016/j.ejmech.2016.12.019

Molecular hybridization yielded phenyl linked oxadiazole-benzohydrazones hybrids 6-35 and were evaluated for their antileishmanial potentials. Compound 10, a 3,4-dihydroxy analog with IC50 value of 0.95 ± 0.01 μM, was found to be the most potent antileishmanial agent (7 times more active) than the standard drug pentamidine (IC50 = 7.02 ± 0.09 μM). The current series 6-35 conceded in the identification of thirteen (13) potent antileishmanial compounds with the IC50 values ranging between 0.95 ± 0.01-78.6 ± 1.78 μM. Molecular docking analysis against pteridine reductase (PTR1) were also performed to probe the mode of action. Selectivity index showed that compounds with higher number of hydroxyl groups have low selectivity index. Theoretical stereochemical assignment was also done for certain derivatives by using density functional calculations.

Matched MeSH terms: Antiprotozoal Agents/chemical synthesis*
Recent Update on the Anti-infective Potential of β-carboline Analogs

Faheem, Kumar BK, Sekhar KVGC, Kunjiappan S, Jamalis J, Balaña-Fouce R, et al.

Mini Rev Med Chem, 2021;21(4):398-425.
PMID: 33001013 DOI: 10.2174/1389557520666201001130114

β-Carboline, a naturally occurring indole alkaloid, holds a momentous spot in the field of medicinal chemistry due to its myriad of pharmacological actions like anticancer, antiviral, antibacterial, antifungal, antileishmanial, antimalarial, neuropharmacological, anti-inflammatory and antithrombotic among others. β-Carbolines exhibit their pharmacological activity via diverse mechanisms. This review provides a recent update (2015-2020) on the anti-infective potential of natural and synthetic β-carboline analogs focusing on its antibacterial, antifungal, antiviral, antimalarial, antileishmanial and antitrypanosomal properties. In cases where enough details are available, a note on its mechanism of action is also added.

Matched MeSH terms: Antiprotozoal Agents/chemical synthesis