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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: Dihydropyridines/chemical synthesis; Dihydropyridines/pharmacology*; Dihydropyridines/chemistry
Fulltext Simple and effective HPLC method development and its validation for Clindipine in human drug free plasma

Muralidharan S, Kumar Jr, Dhanaraj SA

Pak J Pharm Sci, 2015 Jan;28(1):135-8.
PMID: 25553676

Simple and effective high performance liquid chromatographic (HPLC) method was developed for estimation of Clindipine in drug free human drug free blank plasma. The internal standard used as Nifidipine (IS). The current method was used protein precipitating extraction of Clindipine from blank plasma. Separation was achieved on reversed-phase c18 column (25cm × 4.6mm, 5μ) and the detection was monitored by UV detector at 260 nm. The optimized mobile phase was used acetonitrile: 5mM potassium dihydrogen orthophosphate (pH 4.5), in the ratio of 60:40% v/v at a flow rate of 1.0 ml/min. This linearity was achieved in this method range of 10.0-125.0 ng/ml with regression coefficient range is 0.99. The present method is suitable in terms of precise, accurate and specific during the study. The simplicity of the method allows for application in laboratories that lack sophisticated analytical instruments such as LC-MS/MS or GC-MS/MS that are complicated, costly and time consuming rather than a simple HPLC-UV method. The present method was successfully applied for pharmacokinetic studies.

Matched MeSH terms: Dihydropyridines/blood*; Dihydropyridines/pharmacokinetics
Fulltext Efficacy and tolerability of lercanidipine in mild to moderate hypertension among Asians of different ethnic groups

Chia YC, Yeoh ES, Ng CJ, Khoo EM, Chua CT

Singapore Med J, 2009 May;50(5):500-5.
PMID: 19495520

INTRODUCTION: Calcium channel blockers are well established modalities for the treatment of hypertension. However, in spite of the availability of many efficacious agents, hypertension control continues to be poor. One reason is poor tolerability due to adverse events. Racial differences also exist. Lercanidipine, a third-generation calcium channel blocker, is associated with better tolerability. However, it has not been studied in the Asian population. This study examines its efficacy and tolerability in Asian subjects of different ethnicities.
METHODS: This was an eight-week open label study of adults with mild to moderate hypertension. Blood pressure (BP), pulse rate, self-administered symptom check and laboratory evaluations were done at baseline. Patients were prescribed 10 mg lercanidipine, with up-titration to 20 mg if BP was not controlled at Week 4. Baseline evaluations were repeated at Week 8. Adverse events were also enumerated.
RESULTS: 27 patients (mean age 53.4 +/- 12.1 years) completed the study. The baseline systolic BP (SBP), diastolic BP (DBP) and heart rate was 159 +/- 12.2, 96.6 +/- 7.7 mmHg and 71 +/- 13/min, respectively. Three racial groups were represented. SBP and DBP decreased significantly after four weeks of therapy. A further reduction to 139 +/- 14.3 and 88 +/- 9.8 (p-value is less than 0.0001) was seen in Week 8. The absolute SBP and DBP reduction was 20.5 mmHg (95 percent confidence interval [CI] 16.5-24.5, p-value is less than 0.0001) and 9.3 mmHg (95 percent CI 6.2-12.5, p-value is less than 0.0001), respectively. All adverse symptoms, except for palpitations, were reduced at the end of the study.
CONCLUSION: Lercanidipine is efficacious and well tolerated in Asians of different ethnicities. Its BP lowering effects and tolerability in Asians appear to be similar to other studies on Caucasians and other calcium channel blockers.

Matched MeSH terms: Dihydropyridines/adverse effects; Dihydropyridines/therapeutic use*
Molecular basis for resistance to ACCase-inhibiting fluazifop in Eleusine indica from Malaysia

Cha TS, Najihah MG, Sahid IB, Chuah TS

Pestic Biochem Physiol, 2014 May;111:7-13.
PMID: 24861927 DOI: 10.1016/j.pestbp.2014.04.011

Eleusine indica (goosegrass) populations resistant to fluazifop, an acetyl-CoA carboxylase (ACCase: EC6.4.1.2)-inhibiting herbicide, were found in several states in Malaysia. Dose-response assay indicated a resistance factor of 87.5, 62.5 and 150 for biotypes P2, P3 and P4, respectively. DNA sequencing and allele-specific PCR revealed that both biotypes P2 and P3 exhibit a single non-synonymous point mutation from TGG to TGC that leads to a well known Trp-2027-Cys mutation. Interestingly, the highly resistant biotype, P4, did not contain any of the known mutation except the newly discovered target point Asn-2097-Asp, which resulted from a nucleotide change in the codon AAT to GAT. ACCase gene expression was found differentially regulated in the susceptible biotype (P1) and highly resistant biotype P4 from 24 to 72h after treatment (HAT) when being treated with the recommended field rate (198gha(-1)) of fluazifop. However, the small and erratic differences of ACCase gene expression between biotype P1 and P4 does not support the 150-fold resistance in biotype P4. Therefore, the involvement of the target point Asn-2097-Asp and other non-target-site-based resistance mechanisms in the biotype P4 could not be ruled out.

Matched MeSH terms: Dihydropyridines/pharmacology*
The role of multifunctional drug therapy as an antidote to combat experimental subacute neurotoxicity induced by organophosphate pesticides

Singh S, Prakash A, Kaur S, Ming LC, Mani V, Majeed AB

Environ Toxicol, 2016 Aug;31(8):1017-26.
PMID: 25864908 DOI: 10.1002/tox.22111

Organophosphate pesticides are used in agriculture where they are associated with numerous cases of intentional and accidental misuse. These toxicants are potent inhibitors of cholinesterases leading to a massive build-up of acetylcholine which induces an array of deleterious effects, including convulsions, oxidative damage and neurobehavioral deficits. Antidotal therapies with atropine and oxime yield a remarkable survival rate, but fail to prevent neuronal damage and behavioral problems. It has been indicated that multifunction drug therapy with potassium channel openers, calcium channel antagonists and antioxidants (either single-agent therapy or combination therapy) may have the potential to prevent cell death and/or slow down the processes of secondary neuronal damage. The aim of the present study, therefore, was to make a relative assessment of the potential effects of nicorandil (2 mg/kg), clinidipine (10 mg/kg), and grape seed proanthocyanidin (GSPE) extract (200 mg/kg) individually against subacute chlorpyrifos induced toxicity. The test drugs were administered to Wistar rats 2 h after exposure to Chlorpyrifos (CPF). Different behavioral studies and biochemical estimation has been carried in the study. The results showed that chronic administration of CPF significantly impaired learning and memory, along with motor coordination, and produced a marked increase in oxidative stress along with significantly reduced acetylcholine esterase (AChE) activity. Treatment with nicorandil, clinidipine and GSPE was shown to significantly improve memory performance, attenuate oxidative damage and enhance AChE activity in rats. The present study also suggests that a combination of nicorandil, clinidipine, and GSPE has a better neuroprotective effect against subacute CPF induced neurotoxicity than if applied individually. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1017-1026, 2016.

Matched MeSH terms: Dihydropyridines/pharmacology*
Fulltext In-VITRo effect of Ficus deltoidea on the contraction of isolated rat's uteri is mediated via multiple receptors binding and is dependent on extracellular calcium

Salleh N, Ahmad VN

BMC Complement Altern Med, 2013 Dec 14;13:359.
PMID: 24330515 DOI: 10.1186/1472-6882-13-359

BACKGROUND: Ficus deltoidea, is a perennial herb that is used to assist labor, firm the uterus post-delivery and to prevent postpartum bleeding. In view of its claimed uterotonic action, the mechanisms underlying plant's effect on uterine contraction were investigated.
METHODS: Adult female SD rats were injected with 2 mg/kg 17β-oestradiol (E2) to synchronize their oestrous cycle. A day after injection, uteri were removed for in-vitro contraction studies. The dose dependent effect of Ficus deltoidea aqeous extract (FDA) on the tension produced by the isolated rat's uteri was determined. The effects of atropine (2×10(-8) M), atosiban (0.5 IU), THG113.31 (10 μM), oxodipine (0.25 mM), EDTA (1 mM), 2-amino-ethoxy-diphenylborate (2-APB) (40 mM) and thapsigargin (1 mM) on the maximum force of contraction (Emax) achieved following 2 mg/ml FDA administration were also investigated.
RESULTS: FDA induced in-vitro contraction of the isolated rat's uteri in a dose-dependent manner. Administration of atropine, atosiban and THG113.31 reduced the Emax with atosiban having the greatest effect. The Emax was also reduced following oxodipine and EDTA administration. There was no significant change observed following 2-APB administration. Thapsigargin, however, augmented Emax.
CONCLUSIONS: FDA-induced contraction of the isolated rat's uteri is mediated via multiple uterotonin receptors (muscarinic, oxytocin and prostaglandin F2α) and was dependent on the extracellular Ca2+. Contraction, however, was not dependent on the Ca2+ release from the internal stores. This in-vitro study provides the first scientific evidence on the claimed effect of Ficus Deltoidea on uterine contraction.

Matched MeSH terms: Dihydropyridines/pharmacology